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Biological agents such as omalizumab and monoclonal antibodies (mAbs) that inhibit type 2 (T2) immunity significantly reduce exacerbations, which are mainly due to viral infections, when added to inhaled corticosteroids in patients with severe asthma. The mechanisms for the therapeutic benefit of T2 inhibitors in reducing virally induced exacerbations, however, remain to be fully elucidated. Pre-clinical and clinical evidence supports the existence of a close counter-regulation of the high-affinity IgE receptor and interferon (IFN) pathways, and a potential dual mechanism of action and therapeutic benefit for omalizumab and other T2 inhibitors that inhibit IgE activity, which may enhance the prevention and treatment of virally induced asthma exacerbations. Similar evidence regarding some novel T2 inhibitor therapies, including mAbs and small-molecule inhibitors, suggests that such a dual mechanism of action with enhancement of IFN production working through non-IgE pathways might also exist. The specific mechanisms for this dual effect could be related to the close counter-regulation between T2 and T1 immune pathways, and potential key underlying mechanisms are discussed. Further basic research and better understanding of these underlying counter-regulatory mechanisms could provide novel therapeutic targets for the prevention and treatment of virally induced asthma exacerbations, as well as T2- and non-T2-driven asthma. Future clinical research should examine the effects of T2 inhibitors on IFN responses and other T1 immune pathways, in addition to any effects on the frequency and severity of viral and other infections and related exacerbations in patients with asthma as a priority.

Analysing the kinematics of filamentary molecular clouds is a crucial step towards understanding their role in the star formation process. Therefore, we study the kinematics of 283 filament candidates in the inner Galaxy, that were previously identified in the ATLASGAL dust continuum data. The $^{13}$CO(2 - 1) and C$^{18}$O(2 - 1) data of the SEDIGISM survey (Structure, Excitation, and Dynamics of the Inner Galactic Inter Stellar Medium) allows us to analyse the kinematics of these targets and to determine their physical properties at a resolution of 30 arcsec and 0.25 km/s. To do so, we developed an automated algorithm to identify all velocity components along the line-of-sight correlated with the ATLASGAL dust emission, and derive size, mass, and kinematic properties for all velocity components. We find two-third of the filament candidates are coherent structures in position-position-velocity space. The remaining candidates appear to be the result of a superposition of two or three filamentary structures along the line-of-sight. At the resolution of the data, on average the filaments are in agreement with Plummer-like radial density profiles with a power-law exponent of p = 1.5 +- 0.5, indicating that they are typically embedded in a molecular cloud and do not have a well-defined outer radius. Also, we find a correlation between the observed mass per unit length and the velocity dispersion of the filament of $m \sim \sigma_v^2$. We show that this relation can be explained by a virial balance between self-gravity and pressure. Another possible explanation could be radial collapse of the filament, where we can exclude infall motions close to the free-fall velocity., Comment: 45 pages, 20 pages for Table of derived parameters

Importance Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration isrctn.org Identifier: ISRCTN27066620.

We used FIR and submillimeter continuum data from Herschel and the Atacama Pathfinder EXperiment (APEX) to fit pixel-by-pixel modified Planck SEDs to prestellar and protostellar clumps in the Census of High- and Medium-mass Protostars (CHaMP) ($280^{\circ}, Comment: 27 pages, 23 figures (+7 pages, 13 figures in appendix); submitted to MNRAS

RATIONALE: Bronchial epithelial cell damage occurs in patients with bronchial asthma. Ezrin, a membrane-cytoskeleton protein, maintains cellular morphology and intercellular adhesion and protects the barrier function of epithelial cells. OBJECTIVES: To study the role of ezrin in bronchial epithelial cells injury and correlate its expression with asthma severity. METHODS: Levels of ezrin were measured in exhaled breath condensate (EBC) and serum in asthma patients and bronchoalveolar lavage fluid (BALF) from a mouse model of asthma by ELISA. The regulation of IL-13 on ezrin protein levels was studied in primary bronchial epithelial cells (PBECs). Ezrin knockdown using shRNA was studied in human bronchial epithelial 16HBE cells. RESULTS: Ezrin levels were decreased in asthmatic EBC (392.7±34.99 vs 150.5±10.22 pg/ml, p

Kylie BR Belchamber, Catherine MR Thomas, Amy E Dunne, Peter J Barnes, Louise E Donnelly Airway Disease Section, National Heart and Lung Institute, Dovehouse Street, Imperial College London, London, UK Background: Inhaled corticosteroid use is associated with increased rates of pneumonia in COPD patients. The underlying mechanism is unknown, although recent data suggest that pneumonia is more frequent in patients treated with fluticasone propionate (FP) than budesonide. Macrophages and neutrophils from COPD patients are deficient in clearing bacteria, and this might explain increased bacterial colonization in COPD. Inhaled corticosteroid may further suppress this response; therefore, we examined the effect of FP and budesonide on phagocytosis of common respiratory pathogens by monocyte-derived macrophages (MDMs) and neutrophils.Methods: MDMs from COPD patients (n=20–24) were preincubated with FP or budesonide for 1 or 18 hours, after which phagocytosis of fluorescently labeled inert beads or heat-killed Haemophilus influenzae/Streptococcus pneumoniae were measured fluorimetrically after 1 or 4 hours. Additionally, CXCL8, IL6, and TNFα concentrations in supernatants by ELISA, MDM-scavenger-receptor expression by flow cytometry, and MDM ability to kill bacteria were measured. Neutrophils from COPD patients (n=8) were preincubated with corticosteroids for 1 hour and bacteria phagocytosis measured by flow cytometry.Results: After 1 hour’s preincubation, neither corticosteroid altered MDM phagocytosis of beads or H. influenzae; however, budesonide (10-7 M) increased S. pneumoniae phagocytosis by 23% (P

Rationale: In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe exacerbation risk vs terbutaline as-needed, with similar reduction as maintenance BUD + terbutaline as-needed. In a post-hoc analysis of SYGMA 1 (NCT02149199) we examined the short-term risk of a severe exacerbation after a single day at various levels of reliever use, comparing BUD/FORM as-needed vs terbutaline as-needed ± maintenance BUD. Methods: 3836 patients with mild asthma were randomised to placebo twice-daily (bid) + terbutaline 0.5mg as-needed, placebo bid + BUD/FORM 200/6µg as-needed or maintenance BUD 200µg bid + terbutaline as-needed. The proportion of patients with >2, >4, >6 or >8 reliever inhalations on any day, with an exacerbation during the next 21 days were compared. Results: The proportion of patients with >4, >6 or >8 as-needed inhalation use days was lower with BUD/FORM as-needed vs terbutaline as-needed ± maintenance budesonide, with reduced risk of severe exacerbation during the next 21 days vs terbutaline as-needed (Fig). The safety of BUD/FORM as-needed was consistent across all inhalation groups, with no new safety findings. Conclusions: In mild asthma, anti-inflammatory reliever therapy with BUD/FORM as-needed reduces higher (>4 inhalations) reliever use days and reduces exacerbations within the next 21 days vs terbutaline as-needed.

Background: Progressive small airway fibrosis is a key feature of early COPD. In COPD, cellular senescence levels are increased and may relate to disease progression. Peripheral parenchymal fibroblasts are pro-inflammatory and dysfunctional in COPD, but the role of small airway fibroblasts (SAF) and the impact of senescence are unknown. Aim: Compare senescence and pro-fibrotic markers of SAF from COPD patients to age-matched controls. Method: SAF were isolated from non-smoker and COPD surgical lung resections. Gene expression was measured by qPCR, protease activity by zymography, cell proliferation using iCELLigence impedance and senescence cells by senescence-associated β-galactosidase (SA-βGal) staining, p16INK4a and p21Waf1 expression. Results: COPD SAF displayed reduced proliferation (n=4-5, Fig. 1), increased SA-βGal staining (n=6), and elevated p21 (34%) and p16 (12%) expression compared to control non-smoker SAF. Whilst gene expression of MMP2/9 was unchanged (n=3-7), pro-MMP2 was significantly increased (102%, p=0.02) in COPD SAF and similarly trends in elevated pro- and active-MMP2/9 (15-28%). COPD SAF also displayed trends in increased αSMA (25%), COL1A1 (40%) and COL3A1 (20%, n=5) expression. Conclusion: This suggests COPD SAF show cellular senescence, have elevated MMPs and pro-fibrotic markers compared to non-smoker. Elucidating the mechanism underlying this phenotype could lead to future targets of airway fibrosis and COPD.

Background: COPD is now recognised as a disease of accelerated lung aging, associated with increased cellular senescence, mTOR (mammalian target of rapamycin) signalling and decreased expression of anti-aging molecules, such as sirtuin-1/6. AMPK (5’ AMP-activated protein kinase) activation inhibits mTOR, and has been associated with longevity, however its role in regulating senescence in COPD is unclear. Aim: Identify the role of AMPK activation via a pharmacological activator, metformin, on oxidative stress-induced cellular senescence in epithelial cells. Methods: BEAS2B bronchial epithelial cells were exposed to H2O2 (100µM) for 48h +/- metformin. Expression of senescence markers and senescence-associated secretory phenotype (SASP) markers were determined by qPCR and Western blotting. Results: Oxidative stress (H2O2) increased the expression of senescence markers p21 (9-fold, P Conclusion: These data suggest that metformin reverses oxidative stress-induced suppression of sirtuin-1/6 at both the mRNA and protein level, thereby modulating senescence markers. Metformin maybe beneficial in treating accelerated aging in COPD patients.

Adenosine 5′-triphiosphate (ATP) is released from cells under physiologic and pathophysiologic conditions. Extracellular ATP acts as an autocrine and paracrine agent affecting various cell types by activating cell surface P2 receptors (P2R), which include trans-cell membrane cationic channels, P2XR, and G protein coupled receptors, P2YR. We have previously shown that ATP stimulates vagal afferent nerve terminals in the lungs by activating P2X2/3R. This action could lead to bronchoconstriction, cough and the local release of pro-inflammatory neuropeptides. In addition, ATP markedly enhances the IgE-dependent histamine release from human lung mast cells. Thus, we have proposed for the first time that extracellular ATP plays a mechanistic role in pulmonary pathophysiology in general and chronic obstructive pulmonary disease (COPD), and acute bronchoconstriction in asthma in particular. The present review examines whether ATP could also play a role in bradycardia and syncope in a subset of patients with pulmonary embolism.

Background: Isorhapontigenin (trans–3,5,4′-trihydroxy–3′–methoxystilbene, ISO), a dietary resveratrol (trans–3,5,4′–trihydroxystilbene) derivative, possesses various health-promoting activities. To further evaluate its medicinal potentials, the pharmacokinetic and metabolomic profiles of ISO were examined in Sprague-Dawley rats. Methods: The plasma pharmacokinetics and metabolomics were monitored by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–tandem mass spectrometry (GC–MS/MS), respectively. Results: Upon intravenous injection (90 μmol/kg), ISO exhibited a fairly rapid clearance (CL) and short mean residence time (MRT). After a single oral administration (100 μmol/kg), ISO was rapidly absorbed and showed a long residence in the systemic circulation. Dose escalation to 200 μmol/kg resulted in higher dose-normalized maximal plasma concentrations (Cmax/Dose), dose-normalized plasma exposures (AUC/Dose), and oral bioavailability (F). One-week repeated daily dosing of ISO did not alter its major oral pharmacokinetic parameters. Pharmacokinetic comparisons clearly indicated that ISO displayed pharmacokinetic profiles superior to resveratrol as its Cmax/Dose, AUC/Dose, and F were approximately two to three folds greater than resveratrol. Metabolomic investigation revealed that 1-week ISO administration significantly reduced plasma concentrations of arachidonic acid, cholesterol, fructose, allantoin, and cadaverine but increased tryptamine levels, indicating its impact on metabolic pathways related to health-promoting effects. Conclusion: ISO displayed favorable pharmacokinetic profiles and may be a promising nutraceutical in view of its health-promoting properties.

We present $^{12}$CO, $^{13}$CO, and C$^{18}$O data as the next major release for the CHaMP project, an unbiased sample of Galactic molecular clouds in $l$ = 280$^{\circ}$-300$^{\circ}$. From a radiative transfer analysis, we self-consistently compute 3D cubes of optical depth, excitation temperature, and column density for $\sim$300 massive clumps, and update the $I_{\rm CO}$-dependent CO$\rightarrow$H$_2$ conversion law of Barnes et al (2015). For $N$ $\propto$ $I^p$, we find $p$ = 1.92$\pm$0.05 for the velocity-resolved conversion law aggregated over all clumps. A practical, integrated conversion law is $N_{\rm CO}$ = (4.0$\pm$0.3)$\times$10$^{19}$m$^{-2}$ $I_{\rm CO}^{1.27\pm0.02}$, confirming an overall 2$\times$ higher total molecular mass for Milky Way clouds, compared to the standard $X$ factor. We use these laws to compare the kinematics of clump interiors with their foreground $^{12}$CO envelopes, and find evidence that most clumps are not dynamically uniform: irregular portions seem to be either slowly accreting onto the interiors, or dispersing from them. We compute the spatially-resolved mass accretion/dispersal rate across all clumps, and map the local flow timescale. While these flows are not clearly correlated with clump structures, the inferred accretion rate is a statistically strong function of the local mass surface density $\Sigma$, suggesting near-exponential growth or loss of mass over effective timescales $\sim$30-50 Myr. At high enough $\Sigma$, accretion dominates, suggesting gravity plays an important role in both processes. If confirmed by numerical simulations, this sedimentation picture would support arguments for long clump lifetimes mediated by pressure confinement, with a terminal crescendo of star formation, suggesting a resolution to the 40-yr-old puzzle of the dynamical state of molecular clouds and their low star formation efficiency., Comment: Accepted to ApJ. Main paper is 19 pages, plus 4 Appendices which are available from the links on pg.20

BACKGROUND: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β2-agonist may be an alternative to conventional treatment strategies.METHODS: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma.RESULTS: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg).CONCLUSIONS: In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .).

BACKGROUND: Patients with mild asthma often rely on inhaled short-acting β2-agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk.METHODS: We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide-formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire-5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment).RESULTS: A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide-formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide-formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy.CONCLUSIONS: In patients with mild asthma, budesonide-formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide-formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group. (Funded by AstraZeneca; SYGMA 2 ClinicalTrials.gov number, NCT02224157 .).

Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting β2-agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics.Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 μg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 μg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 μg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 μg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured.Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25−75% and FEV1/FVC (P = 0.008–0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01).Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42.

Severe asthma is heterogeneous clinically and biologically and is often difficult to control. In particular, the type 2 (T2) immunity endotype of severe asthma is gaining increasing interest because it is susceptible to newly developed biologic treatments that can transform the quality of life of these patients. The aim of this study was to analyze periostin concentrations in the airways of patients with severe asthma, evaluating its role in clustering the T2 endotype.We enrolled 40 consecutive patients with severe asthma (T2 endotype: n = 25; non-T2 endotype: n = 15), 21 patients with mild to moderate asthma, and 15 healthy control subjects. All subjects enrolled underwent exhaled breath condensate (EBC) and sputum collection, eosinophil count in blood, fractional exhaled nitric oxide, and IgE measurement. Periostin was assessed by an enzyme-linked immunosorbent assay kit on EBC and induced sputum (IS) supernatant.We were able to detect higher periostin levels in the EBC (0.75 ± 0.46 vs 0.70 ± 0.19 vs 0.11 ± 0.05 ng/mL, P .05 and P .01) and in IS (0.55 ± 0.23 vs 0.31 ± 0.13 vs 0.16 ± 0.120 ng/mL, P .05 and P .01) of patients with severe asthma compared with patients with mild to moderate asthma and healthy control subjects, respectively. We further found an increase of periostin levels in both samples in T2 endotype compared with non-T2 endotype (EBC: 0.88 ± 0.46 vs 0.52 ± 0.46 ng/mL; IS: 0.69 ± 0.19 vs 0.39 ± 0.16 ng/mL; P .05) and a correlation between periostin levels in EBC and sputum.We found that periostin is measurable in the airways and increased in patients with severe asthma, especially in those from the T2 endotype. Unlike serum periostin, which may be derived from several sources outside the lung, airways periostin is a useful marker of severe eosinophilic asthma and may help to phenotype patients that will respond to the biologic agents.

This study evaluated the loss of Klotho in human lungs with COPD and the underlying mechanisms., COPD (chronic obstructive pulmonary disease) is associated with sustained inflammation, excessive injury, and accelerated lung aging. Human Klotho (KL) is an anti-aging protein that protects cells against inflammation and damage. In the present study, we quantified KL expression in the lungs of COPD patients and in an ozone-induced mouse model of COPD, and investigated the mechanisms that control KL expression and function in the airways. KL distribution and levels in human and mouse airways were measured by immunohistochemistry and Western blotting. The effect of CSE (cigarette smoke extract) on KL expression was detected in human bronchial epithelial cells. Moreover, the effect of KL on CSE-mediated inflammation and hydrogen peroxide-induced cellular injury/apoptosis was determined using siRNAs. KL expression was decreased in the lungs of smokers and further reduced in patients with COPD. Similarly, 6 weeks of exposure to ozone decreased KL levels in airway epithelial cells. CSE and TNFα (tumour necrosis factor α) decreased KL expression and release from airway epithelial cells, which was associated with enhanced pro-inflammatory cytokine expression. Moreover, KL depletion increased cell sensitivity to cigarette smoke-induced inflammation and oxidative stress-induced cell damage. These effects involved the NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and Nrf2 (nuclear factor erythroid 2-related factor 2) pathways. Reduced KL expression in COPD airway epithelial cells was associated with increased oxidative stress, inflammation and apoptosis. These data provide new insights into the mechanisms associated with the accelerated lung aging in COPD development.

Current rhinometric and flow assessments measure nasal patency and are often poorly correlated with rhinitis symptoms. To evaluate magnetic resonance imaging (MRI) as a new method to measure inflammatory changes in nasal and sinus mucosa following nasal allergen challenge. A pilot study (n = 6) determined the optimal technical settings for MRI to measure inflammatory change which were then adopted for the main study. This study was a single blind, placebo-controlled, three-way crossover trial in 14 subjects with seasonal allergic rhinitis. Effects of cetirizine, cetirizine and pseudoephedrine (Cet+PE), or placebo on total nasal symptom scores (TNSS), peak nasal inspiratory flow (PNIF), nasal nitric oxide (nNO), acoustic rhinometry, and MRI end points following nasal intranasal allergen challenge were measured. There were significant changes in all parameters after allergen challenge (P 0.07; comparison of active versus placebo P > 0.09). MRI provides novel insights into the anatomical inflammatory changes post allergen challenge and provides a new method for assessment of nasal patency and objective measurement of inflammatory responses.

We report new imaging polarimetry observations of the Galactic compact HII region K3-50 using CanariCam at the Gran Telescopio Canarias. We use a standard polarimetric analysis technique, first outlined by Aitken, to decompose the observed polarisation images centred at 8.7, 10.3, and 12.5 $\mu$m into the emissive and absorptive components from silicate grains that are aligned with the local magnetic field. These components reveal the spatially-resolved magnetic field structures across the mid-infrared emission area of K3-50. We examine these structures and show that they are consistent with previously observed features and physical models of K3-50, such as the molecular torus and the ionised outflow. We propose a 3D geometry for all the structures seen at different wavelengths. We also compute relevant physical quantities in order to estimate the associated magnetic field strengths that would be implied under various physical assumptions. We compare these results with MHD simulations of protostar formation that predict the magnetic field strength and configuration. We find that the magnetic field may be dynamically important in the innermost 0.2 pc of the molecular torus, but that the torus is more likely to be rotationally-supported against gravity outside this radius. Similarly, magnetic fields are unlikely to dominate the {\em global} physics of the ionised outflow, but they may be important in helping confine the flow near the cavity wall in some locations. Ours is the first application of the Aitken technique to spatially-resolved magnetic field structures in multiple layers along the line of sight, effectively a method of "polarisation tomography.", Comment: 15 pages, 12 figures, accepted by MNRAS

The recognition that there are some patients with features of asthma and chronic obstructive pulmonary disease (COPD) has highlighted the need to develop more specific treatments for these clinical phenotypes. Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness.

BACKGROUND The forced oscillation technique (FOT) measures respiratory resistance and reactance; however, the upper airways may affect the results. We quantified the impact of glottal aperture and buccal air leaks. METHODS In the glottal aperture study (1) 10 healthy subjects (aged 34 ± 2 years) performed a total lung capacity maneuver followed by 10-s breath-hold with and without total glottal closure and (2) the effects of humming (incomplete glottal narrowing) on FOT measurements were studied in six healthy subjects. Glottal narrowing was confirmed by direct rhinolaryngoscopy. In the air leak study, holes of increasing diameter (3.5, 6.0, and 8.5 mm) were made to the breathing filters. Eleven healthy subjects (aged 33 ± 2 years) and five patients with COPD (aged 69 ± 3 years) performed baseline FOT measurements with the three modified filters. RESULTS Narrow glottal apertures and humming generated whole-breath resistance at 5 Hz (R5) peaks, increased R5 (1.49 ± 0.37 kPa/L/s vs 0.34 ± 0.01 kPa/L/s, P ≤ .001), and decreased whole-breath reactance at 5 Hz (X5) values (−2.10 ± 0.51 kPa/L/s vs −0.09 ± 0.01 kPa/L/s, P≤ .001). The frequency dependency of resistance was increased. Holes in the breathing filters produced indentations on the breathing trace. Even the smaller holes reduced R5 in healthy subjects (0.33 ± 0.02 to 0.24 ± 0.02 kPa/L/s, P ≤ .01) and patients with COPD (0.50 ± 0.04 to 0.41 ± 0.04 kPa/L/s, P≤.05), whereas X5 became less negative (from −0.09 ±0.01 to −0.05 ± 0.01 in healthy subjects, P ≤.01; from −0.22 ± 0.06 to −0.11 ± 0.03 kPa/L/s in patients with COPD, P ≤ .05). CONCLUSIONS Visual inspection of the data is required to exclude glottal narrowing and buccal air leaks identified as R5 peaks and volume indentations, respectively, because these significantly affect FOT measurements.

There is an urgent need to develop more effective therapies for chronic obstructive pulmonary disease (COPD) that target the underlying inflammatory disease process. Current therapies with long-acting bronchodilators and inhaled corticosteroids fail to prevent either disease progression or mortality, as they do not suppress the underlying inflammation. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing. Broad-spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus-activated kinases, NF-κB kinase, and PI3kinase-γ and -δ, but side effects after oral administration are a major limitation; therefore, in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 activity. This might be achieved by existing treatments such as theophylline, nortriptyline, and macrolides, or more selectively by PI3kinase-δ inhibitors. Other treatments in development target oxidative stress, the failure to resolve inflammation, aberrant repair mechanisms, and accelerated lung aging.

BACKGROUND Extracellular adenosine 5′-triphosphate (ATP) stimulates vagal C and Ad fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers, and patients with COPD and compared these responses to the effects of inhaled adenosine, the metabolite of ATP. METHODS We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity, and ATP in exhaled breath condensate in healthy nonsmokers (n = 10), healthy smokers (n = 14), and patients with COPD (n = 7). RESULTS In comparison with healthy subjects, ATP induced more dyspnea, cough, and throat irritation in smokers and patients with COPD, and the effects of ATP were more pronounced than those of AMP. The concentration of ATP in the exhaled breath condensate of patients with COPD was elevated compared with that of healthy subjects. CONCLUSIONS Smokers and patients with COPD manifest hypersensitivity to extracellular ATP, which may play a mechanistic role in COPD. CHEST 2015;148(2):430-435

BACKGROUND Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma. METHODS Thirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV 1 , and symptoms using the COPD Assessment Test (CAT). RESULTS At 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, –16.4 pg/mL, P = .01; –48.6 pg/mL, P .001; –45.3 pg/mL, P = .002; and –190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P .001; 1.02, P .001; and 0.47, P .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, –0.16 × 10 6 , P = .004; –14.1%, P .001; and –3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments. CONCLUSIONS Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov

The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases.

International audience; Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes. @ERSpublications ATS/ERS statement: which types of research will have the greatest future impact on patient-centred outcomes in COPD? http://ow.ly/I54Hb

The rise in life expectancy worldwide has been accompanied by an increased incidence of age-related diseases, representing an enormous burden on healthcare services and society. All vital organs lose function with age, and this is well described in the lung, with a progressive decline in pulmonary function after the age of about 25 years. The lung ages, like any other organ, with progressive functional impairment and reduced capacity to respond to environmental stresses and injury. Normal physiological ageing results in enlarged alveolar spaces and loss of lung elasticity in the elderly known as 'senile emphysema', whereas in COPD there is destruction of the alveolar walls and fibrosis of peripheral airways. However, COPD shows striking age-associated features, such as an increase in cellular senescence, stem cell exhaustion, increased oxidative stress, alteration in the extracellular matrix and a reduction in endogenous antiageing molecules and protective pathways such as autophagy. In this review we discuss the evidence showing how oxidative stress induces accelerated ageing by upregulating the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT/mechanistic target of rapamycin signalling pathway resulting in depletion of stem cells, defective autophagy, reduced antioxidant responses and defective mitochondrial function thus generating further oxidative stress. Understanding the mechanisms of accelerated ageing in COPD may identify novel therapeutic approaches.

AIMS: To establish the dose-response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulised formulation of the long-acting muscarinic antagonist glycopyrrolate (EP-101) with a high efficiency nebuliser in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with moderate to severe COPD (GOLD II/III), with reversible lung function were enrolled into this randomised, double-blind, placebo-controlled, 6-period cross-over study (n=42). Patients received single doses of EP-101 (12.5-400?g) and placebo via a high efficiency nebuliser (eFlow(�) PARI nebuliser), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n=11). RESULTS: All treatments were well tolerated with similar adverse event rates reported with placebo and at all doses. There were no clinically relevant changes in heart rate, systolic and diastolic blood pressure or in ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5?minutes. Significant improvements in mean change from baseline FEV1 at 24 hours were reported at doses >50?g compared with placebo, with a clear dose response relationship. Mean change in FEV1 were 0.10L (0.06-0.14 95%CI) and 0.12L (0.08-0.16) for 100?g and 200?g respectively. CONCLUSION: Single doses of EP-101 ranging from 12.5?g to 400?g were well tolerated. EP-101 delivered by high efficiency nebuliser device produced a rapid onset of bronchodilatation with clinically meaningful improvements in lung function maintained over a 24 hour period at all doses >50?g.

Background Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting β2-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking. Objective To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma. Methods We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation. Results Six RCTs (n = 1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR = 0.56, P = 0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR = 1.39, P = 0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR = 0.52, P = 0.002) but had no difference when compared with ICS regimen (HR = 1.30, P = 0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen. Conclusions Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings.

Lower airway colonisation with species of potentially pathogenic bacteria (PPB) is associated with defective bacterial phagocytosis, in monocyte-derived macrophages (MDMs) and alveolar macrophages, from tobacco smoke-associated chronic obstructive pulmonary disease (S-COPD) subjects. In the developing world, COPD among nonsmokers is largely due to biomass smoke (BMS) exposure; however, little is known about PPB colonisation and its association with impaired innate immunity in these subjects.We investigated the PPB load (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Pseudomonas aeruginosa) in BMS-exposed COPD (BMS-COPD) subjects compared with S-COPD and spirometrically normal subjects. We also examined the association between PPB load and phagocytic activity of MDMs and lung function. Induced sputum and peripheral venous blood samples were collected from 18 healthy nonsmokers, 15 smokers without COPD, 16 BMS-exposed healthy subjects, 19 S-COPD subjects and 23 BMS-COPD subjects. PPB load in induced sputum and MDM phagocytic activity were determined using quantitative PCR and fluorimetry, respectively.Higher bacterial loads of S. pneumoniae, H. influenzae and P. aeruginosa were observed in BMS-COPD subjects. Increased PPB load in BMS-exposed subjects was significantly negatively associated with defective phagocytosis in MDMs and spirometric lung function indices (pIncreased PPB load in airways of BMS-COPD subjects is inversely associated with defective bacterial phagocytosis and lung function.

Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected frompatients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence orabsence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC frompatients with COPD showed corticosteroid insensitivity comparedwith those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD.

Background Current guidelines recommend a single inhaler maintenance and reliever therapy (SMART) regimen for moderate to severe asthma. However, evidence for the inhaled corticosteroid plus fast-onset-acting β2-agonist (ICS/FABA) as reliever therapy in management of intermittent and mild asthma patients is lacking. Objective To systematically explore efficacy and safety of the proof-of-concept of the ICS plus FABA regimen in a single inhaler as reliever therapy across children and adults with intermittent and mild persistent asthma. Methods We searched online bibliographic databases for randomized controlled trials (RCTs) involving the as-needed use of ICS/FABA as monotherapy in intermittent or mild asthma patients. The primary outcomes were exacerbations and the hazard ratio (HR) of the time to first exacerbation. Results Six RCTs (n = 1300) met the inclusion criteria. Compared with the as-needed FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced exacerbations (RR = 0.56, P = 0.001). Compared with regular ICS regimen, the as-needed ICS/FABA therapy had slightly higher risk of exacerbations (RR = 1.39, P = 0.011). The HR for time to first exacerbations in the ICS/FABA regimen was significant lower when compared with FABA regimen (HR = 0.52, P = 0.002) but had no difference when compared with ICS regimen (HR = 1.30, P = 0.286). The corticosteroid exposure in the daily ICS regimen was 2- to 5-fold compared with as-needed use of ICS/FABA regimen. Conclusions Our analysis shows that the ICS/FABA as a symptom-driven therapy may be a promising alternative regimen for the patients with intermittent or mild asthma, but it needs further real-world RCTs to confirm these findings. Electronic supplementary material The online version of this article (10.1186/s12931-017-0687-6) contains supplementary material, which is available to authorized users.

Electronic cigarettes (e-cigs) are used as smoking cessation tools, but limited data exist on their biological effects. Chronic tobacco smoking alters macrophage (Mφ) function, resulting in impaired phagocytosis and altered cytokine release; it is possible that e-cigs similarly affect Mφ function. This study compared the effects of e-cigs compared to cigarettes on Mφ function. Six e-cigs (tobacco flavoured ± nicotine, banoffee pie flavoured ± nicotine, vehicle, or nicotine + vehicle) or 1 cigarette were ‘smoked’ for 2.5 min into media to generate e-cig vapour extract (e-CVE) or cigarette smoke extract (CSE). Monocyte-derived Mφ (N=6) cultured from healthy volunteers, were incubated for 24h with e-CVE or CSE, incubated for 4h with fluorescently-labelled H.influenzae or S.pneumoniae , and phagocytosis measured fluorimetrically, and TNFα, CXCL8 and IL-6 by ELISA. Expression of toll-like receptors (TLR)-2 and -4, and MARCO were measured by flow cytometry and cell viability by MTT assay. Neither CSE nor e-CVE affected cell viability or altered phagocytosis, though higher concentrations of CSE tended towards reduced phagocytosis. TNFα release was significantly reduced by CSE (72±4%, p Flavoured e-CSE caused similar changes to Mφ cytokine release as CSE. E-CSE vehicle and nicotine alone had no effect, suggesting a constituent of flavourings are inhibitory. This hightlights the need for further study of e-cigs on lung health.

Culture independent techniques have allowed a better understanding of association between tobacco-smoke exposed COPD (TS-COPD) & lung microbiome, but there is limited knowledge about lung microbiome in non-smoker COPD (NS-COPD) subjects. We aimed to study lung microbiome in smoker & non-smoker COPD subjects and its association with lung function in rural Indian subjects. Induced sputum samples were obtained from 11 healthy-nonsmokers (H-Nonsmokers), 10 healthy-smokers (H-Smokers), 18 biomass-smoke exposed healthy (H-Biomass), 15 TS-COPD & 20 NS-COPD subjects. Samples were sequenced using V3 & V4 hypervariable region (Illumina MiSeq Platform) and taxanomic diversity information was obtained with QIIME pipeline, & R script package. Bacterial abundance was significantly higher in NS-COPD subjects compared to H-Nonsmokers, H-Biomass, & TS-COPD subjects (Fig.1A). Exposure to tobacco-smoke caused decrease in bacterial diversity (Fig.1B). Firmicutes, Bacteriodetes, Proteobacteria, Actinobcater & Fusobacter were the most prevalent phyla in our samples. Phylum Proteobacteria, which includes many pathogens showed higher abundance in COPD subjects (Fig.1C) & were negatively associated with lung function (Fig.1D). The impaired lung function observed in COPD is associated with in increased abundance of pathogenic microbiome & a decline in its diversity, which may have implications in COPD pathophysiology.

Background: COPD is a disease of accelerated lung aging and is associated with elevated cellular senescence. Increased senescent fibroblasts are seen in small airways of patients with COPD, which may contribute to disease progression via progressive fibrosis and release of pro-inflammatory cytokines. However, mechanisms by which senescence is induced in these cells are unclear. Aims: To investigate the role of miR-34a in small airway fibroblast (SAF) senescence in non-smokers and COPD patients. Methods: SAFs were isolated from human lung resection tissue from non-smokers and COPD patients and the expression of miR-34a and senescence markers measured by qPCR. SAFs were treated with miR-34a inhibitors or mimics and changes in senescence markers compared to the scrambled control. Senescence was detected using β-galactosidase staining and iCELLigence technology used to assess cell proliferation. Results: COPD SAFs (n=5) showed increased expression of miR-34a (2-fold), p21 (6-fold) and p27 (2-fold) compared to non-smokers (n=5). COPD SAFs displayed elevated β-galactosidase staining and impaired proliferation compared to non-smoker SAFs. In non-smoker SAFs (n=3), a miR-34a mimic suppressed SIRT1 expression by 44% but increased p21 and p27 by 1.3-fold. Similarly in COPD SAFs, SIRT1 was reduced by 37% and p21 and p27 elevated 1.4 and 1.7-fold, respectively. Conversely, the miR-34a inhibitor (antagomir, n=5) reduced p21 by 15% and 25% in non-smoker and COPD SAFs respectively. Conclusions: These data suggest greater senescence in COPD SAFs compared to controls, with miR-34a contributing to changes in senescent markers, therefore suggesting miR-34a as a future therapeutic target for accelerated aging disease such as COPD.

The Global initiative for chronic Obstructive Lung Disease (GOLD) Strategy is a valuable tool for clinicians in the diagnosis and management of patients with established chronic obstructive pulmonary disease (COPD). However, there are no recommendations for the evaluation of individuals, exposed to risk factors, who are most likely to develop COPD. Consequently, it is necessary to consider all of the factors that may play a role in the pathogenesis of COPD: genetic factors, gender, socioeconomic status, disadvantageous factors in childhood, lung diseases and exposure to risk factors such as smoking, biomass fuel smoke, occupational hazards and air pollution. Along with the clinical assessment, periodic spirometry should be performed to evaluate lung function and make possible early detection of individuals who will develop the disease through the rate of forced expiratory volume in 1 second (FEV1) decline. The first spirometry, periodicity, and clinically significant decline in FEV1 will encompass the cornerstones of clinical follow up. This approach allows the implementation of important interventions in order to help individuals to cease contact with risk factors and prevent progressive respiratory impairment with the consequent deterioration of quality of life and increased morbidity and mortality.

We measured mid-infrared polarization of protoplanetary discs to gain new insight into their magnetic fields. Using CanariCam at the 10.4 m Gran Telescopio Canarias, we detected linear polarization at 8.7, 10.3, and 12.5 $\mu$m from discs around eight Herbig Ae/Be stars and one T-Tauri star. We analyzed polarimetric properties of each object to find out the most likely interpretation of the data. While the observed mid-infrared polarization from most objects is consistent with polarized emission and/or absorption arising from aligned dust particles, we cannot rule out polarization due to dust scattering for a few objects in our sample. For those objects for which polarization can be explained by polarized emission and/or absorption, we examined how the derived magnetic field structure correlates with the disc position angle and inclination. We found no preference for a certain type of magnetic field. Instead, various configurations (toroidal, poloidal, or complex) are inferred from the observations. The detection rate (64 per cent) of polarized mid-infrared emission and/or absorption supports the expectation that magnetic fields and suitable conditions for grain alignment are common in protoplanetary discs around Herbig Ae/Be stars., Comment: 14 pages, 4 figures; accepted for publication in MNRAS

BACKGROUND: Bronchiectasis is characterized by abnormal and permanent dilation of the bronchi, caused by the perpetuation of inflammation and impairment of mucociliary clearance. Physiotherapy techniques can help to decrease the retention of respiratory secretions. The flutter valve combines high-frequency oscillation and positive expiratory pressure to facilitate the removal of secretions. We evaluated the effects of the flutter valve on sputum inflammation, microbiology, and transport of respiratory secretions in patients with bronchiectasis. METHODS: Seventeen participants underwent sessions with flutter or control (flutter-sham), for 30 min/d, in a randomized crossover study, with 4 weeks with one of the therapies, a 2-week wash-out period, and then another 4 weeks with the other modality. Secretion samples were collected every week throughout the protocol and were assessed for the mucociliary transport, displacement in a simulated cough machine, contact angle, and cell cytology with percentage of neutrophil count, eosinophils, and macrophages, and the microbiology was assessed by the number of colony-forming units. RESULTS: Treatment with flutter resulted in greater displacement in a simulated cough machine and smaller contact angle, comparing the results between the first week (9.94 ± 3.12 cm and 26.5 ± 3.21°, respectively) and fourth week of treatment (13.96 ± 5.76 cm and 22.76 ± 3.64°, respectively) and was associated with a decrease in the total number of inflammatory cells. CONCLUSIONS: The use of a flutter valve for 30 min/d for at least 4 weeks is enough to change physical properties and improve mucus transport by coughing and can contribute to the reduction of the total number of inflammatory cells of the respiratory secretions of subjects with bronchiectasis. (ClinicalTrials.gov registration NCT01209546.)

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria. Objectives: The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated. Methods: AMs were obtained from bronchoalveolar lavage from healthy donors or patients with COPD and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line in which the CD68 promoter ensures macrophage-specific expression of human induced myeloid leukemia cell differentiation protein Mcl-1 (CD68.hMcl-1) was used to model the molecular aspects of COPD. Measurements and Main Results: COPD AMs had elevated levels of Mcl-1, an antiapoptotic B-cell lymphoma 2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AMs phenocopied the microbicidal defect because transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow–derived macrophages and human monocyte-derived macrophages generated mROS in response to pneumococci, which colocalized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected bone marrow–derived macrophages but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AMs also increased basal mROS expression, but they failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS/superoxide dismutase 2. Conclusions: Up-regulation of Mcl-1 and chronic adaption to oxidative stress alter mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD.

Airway remodelling is an important component of chronic obstructive pulmonary disease (COPD). Neutrophil gelatinase-associated lipocalin (NGAL) from neutrophils may drive COPD epithelial–mesenchymal transition (EMT). NGAL expression was quantified in the lungs of COPD patients and bronchoalveolar lavage fluid (BALF) of ozone-treated mice. Reticular basement membrane (RBM) thickness and E-cadherin and α-smooth muscle actin (α-SMA) expression were determined in mice airways. Effects of cigarette smoke extract (CSE) and inflammatory factors on NGAL expression in human neutrophils as well as the effects of NGAL on airway structural cells was assessed. NGAL was mainly distributed in neutrophils and enhanced in lung tissues of both COPD patients and BALF of ozone-treated mice. We showed decreased E-cadherin and increased α-SMA expression in bronchial epithelium and increased RBM thickness in ozone-treated animals. In vitro, CSE, IL-1β and IL-17 enhanced NGAL mRNA expression in human neutrophils. NGAL, in turn, down-regulated the expression of E-cadherin and up-regulated α-SMA expression in 16HBE cells via the WNT/glycogensynthase kinase-3β (GSK-3β) pathway. Furthermore, NGAL promoted the proliferation and migration of human bronchial smooth muscle cells (HASMCs). The present study suggests that elevated NGAL promotes COPD airway remodelling possibly through altered EMT. NGAL may be a potential target for reversing airway obstruction and remodelling in COPD.