The ion channel transient receptor potential melastatin-2 does not play a role in inflammatory mouse models of chronic obstructive pulmonary diseases

<p>Abstract</p> <p>Background</p> <p>There is strong evidence that oxidative stress is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). The transient receptor potential melastatin-2 (TRPM2) is an oxidative stress sensing channel that is expressed in a number of inflammatory cells and therefore it has been suggested that inhibition of TRPM2 could lead to a beneficial effect in COPD patients. In this study, we have investigated the role of TRPM2 in a variety of mouse models of oxidative stress and COPD using TRPM2-deficent mice.</p> <p>Methods</p> <p>Mice were exposed to ozone (3 ppm for 4 h) or lipopolysaccharide (LPS, 0.3 mg/kg, intranasaly). In another model, mice were exposed to tobacco smoke (750 μg/l total wet particulate matter) for 30 min twice a day on three consecutive days. For the exacerbation model, the smoke exposure on the morning of day 3 animals was replaced with intranasal administration of LPS (0.3 mg/kg). Animals were killed 3 and 24 h after the challenge (ozone and LPS model) or 18 h after the last tobacco smoke exposure. In vitro neutrophil chemotaxis and monocyte activation were also studied using cells isolated from wild type and TRPM2-deficient animals. Statistical significance for the in vivo data (<it>P </it>< 0.05) was determined using analysis of variance with Kruskal-Wallis and Dunns multiple comparison test.</p> <p>Results</p> <p>In all models studied, no difference in the bronchoalveolar lavage inflammation could be evidenced when comparing wild type and TRPM2-deficient mice. In addition, no difference could be seen in the lung inflammation as assessed by the measurement of various cytokines/chemokines. Similarly in various in vitro cellular activation assays using isolated neutrophils and monocytes no significant differences could be observed when comparing wild type and TRPM2-deficient mice.</p> <p>Discussion</p> <p>We have shown, in all the models tested, no difference in the development of airway inflammation or cell activation between TRPM2-deficient mice and their wild type counterparts. These results would suggest that inhibiting TRPM2 activity in COPD would have no anti-inflammatory effect.</p

Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations

BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist [LAMA])/vilanterol (VI; long-acting beta2-agonist [LABA]) and fluticasone propionate/salmeterol (FP/SAL) (inhaled corticosteroid/LABA) are approved maintenance therapies for chronic obstructive pulmonary disease (COPD). Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year. METHODS: In these 12-week, multicenter, double-blind, parallel-group, double-dummy trials, randomized (1:1) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg (DB2114930 n = 353 and 353; DB2114951 n = 349 and 348, respectively; intent-to-treat). Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, dyspnea, quality of life (QoL) and safety. RESULTS: UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures versus FP/SAL. For 0-24 h wmFEV1 (Day 84), improvements with UMEC/VI versus FP/SAL were 74 mL (95% confidence interval [CI]: 38-110; DB2114930) and 101 mL (63-139; DB2114951) (both p 1 unit) and QoL (St George's Respiratory Questionnaire Total score >4-unit decrease) in both studies with no statistical differences between treatments. Adverse event rates were similar: 26 and 30% UMEC/VI; 27 and 31% FP/SAL. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION: DB2114930/NCT01817764; DB2114951/NCT01879410

Study on comprehensive policy review of anti-trafficking projects funded by the European Commission:HOME/2014/ISFP/PR/THBX/0052

This report addresses four objectives: 1. To conduct a comprehensive review of European Commission (EC) funded anti-trafficking projects so as to enhance coordination, avoid duplication and provide a solid basis for coherent, cost-effective and strategic planning, including potentially for the further development of anti-trafficking policies at EU level, thereby supporting the dual aims of enhanced coordination and cooperation among key actors and policy coherence. 2. To map and analyse the distribution of EC-funded anti-trafficking projects according to their scope of intervention, geographic areas of intervention, fields, actors, target beneficiaries, funding level, types of output, policy recommendations and other relevant aspects. 3. To identify and assess the common, unique or complementary contribution of the impact and results of these funded projects to the objectives of the EU anti-trafficking strategy, including whether their contribution has yet been taken into account. 4. To identify trends, emerging research and policy question

Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial.

Study design Figure. Abbreviations: BDI, Baseline Dyspnoea Index; CAT, COPD Assessment Test; FP/SAL, fluticasone propionate/salmeterol; FEV1, forced expiratory volume in 1 s; ITT, intent-to-treat; mMRC, modified Medical Research Council SGRQ-C, St George’s Respiratory Questionnaire for COPD; TDI, Transition Dyspnoea Index; UMEC, umeclidinium; VI, vilanterol. (PDF 425 kb

Effects of a combination of subchronic tobacco smoke exposure and lipopolysaccharide administration on pulmonary inflammation in the mouse

Chronic Obstructive Pulmonary Disease (COPD) is characterised by a predominantly irreversible restriction of airflow and often by acute exacerbations (AECOPD). These exacerbations are defined as a worsening of symptoms that result in a need to alter medication and are associated with an altered inflammatory response and a decline in lung function. Tobacco smoking is widely accepted as the main causative agent for COPD, with the majority of exacerbations being associated with subsequent bacterial or viral infection. Our aim was to develop a model that would mimic aspects of the altered inflammatory response observed in a bacteria-induced AECOPD. We combined multiple wholebody tobacco smoke (TS) exposures with the administration of the bacterial mimetic lipopolysaccharide (LPS). Each week for the first five weeks, female Balb/c mice (n=8-10 per group) were exposed twice a day to 30 minutes of either TS (750µg/l wet total particulate matter) or room air (RA) on days 1-5. On days 6 and 7 they were rested. During week six, the protocol was the same for the first two days. On the morning of day three LPS (0.3mg/kg; E.coli 0111:B4) or saline (0.9%w/v) were administered intranasally under isoflurane anaesthesia followed 5 hours later by TS or RA exposure. Twenty four hours after LPS administration animals were terminally anaesthetised (Fentanyl citrate 0.8mg/kg, Fluanisone 25mg/kg and Midazolam 12.45mg/kg i.p.) and the trachea cannulated. Bronchoalveolar lavage (BAL) was then performed to assess cell influx (Table1), cytokine levels and cytotoxicity. Data are expressed as the mean ±SEM with n=8-10 animals per group. BAL total cells were elevated in mice exposed to the combination of LPS and TS compared to those exposed to TS alone. However, the increase in total cells, compared to RA/saline controls, was lower in the mice exposed to LPS/TS compared to those exposed to LPS alone (Table 1). Neutrophils showed a comparable profile. Interleukin-6 (IL-6) concentrations in the BAL were significantly elevated in the RA/LPS (1687±176pg/ml) animals compared to RA/Saline (57±9 pg/ml) mice. They were also significantly elevated in the TS/LPS animals (745±125 pg/ml) but to a lesser extent. Interleukin-1β and keratinocyte cytokine (KC) showed similar profiles. Lactate dehydrogenase (LDH) activity, a marker of cytotoxicity, was highest in the BAL of TS/LPS treated animals (1.9±0.3 absorbance units (AU)) compared with either the RA/LPS animals (1.3±0.2AU), the TS/Saline mice (0.9±0.1) or the RA/Saline mice (0.2±0). These data indicate that certain aspects of the inflammatory response to LPS are reduced after 6 weeks TS exposure. This animal model may be useful for investigating the altered inflammatory response observed during an AECOPD. Table 1: Effect of LPS and tobacco smoke exposure on cell numbers in the BAL. Treatment groups RA/Saline RA/LPS TS/Saline TS/LPS Total cells 100 ± 14 1438 ±167(###) 477 ± 31 992 ± 166(###) Neutrophils 2 ± 1 1253 ± 155(###) 267 ± 19 736 ± 128(###) Macrophages 98 ± 14 183 ± 30 208 ± 23(#) 256 ± 47(##) Data expressed as mean cells x 103/ml ± sem. (Kruskal-Wallis followed by Dunn’s post test was used # p<0.05, ## p<0.01, ### p<0.001 compared to RA/Saline control

Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial

Abstract Background Umeclidinium (UMEC; long-acting muscarinic antagonist) plus vilanterol (VI; long-acting beta2 agonist [LABA]) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol (FP/SAL) are approved maintenance treatments for chronic obstructive pulmonary disease (COPD). This 12-week, multicentre, double-blind, parallel-group, double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment. Methods Patients (n = 717) were randomised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg. Endpoints included 0–24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, symptoms, quality of life (QoL) and safety. Results Improvements with UMEC/VI versus FP/SAL were 0.080 L (95 % confidence interval: 0.046–0.113; wmFEV1) and 0.090 L (0.055–0.125; trough FEV1) (both p < 0.001). UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL. Both treatments demonstrated a clinically meaningful improvement in symptoms (Transition Dyspnoea Index ≥1 unit) and QoL (St George’s Respiratory Questionnaire Total score ≥4 unit decrease from baseline) over 12 weeks. The incidence of adverse events was 28 % (UMEC/VI) and 29 % (FP/SAL); nasopharyngitis and headache were most common. Conclusions Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment. Trial Registration NCT01822899 Registration date: March 28, 201