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Background: Pulmonary rehabilitation (PR) is an important therapy for patients with chronic obstructive pulmonary disease (COPD), yet uptake remains low. Intervention strategies which recapitulate the benefits of PR are, therefore, needed and digital, home-based therapies present opportunity in this space. Digital therapies also potentially offer an opportunity to standardize PR in clinical trials for new COPD therapies. Aims and Methods: We aimed to create a digital application (app), Respercise(®), consisting of up to 4 strengthening exercises in conjunction with Therbands™ and a daily physical activity program with individualized step goals, and to test its feasibility in a clinical trial. App usability was surveyed qualitatively before development iterations and deployment in a 13-week interventional clinical trial. All participants who completed the study were invited for an exit interview and performed the 5-repetition sit-to-stand test amongst other measures. Results: Feedback from clinical trial participants was positive; 97% of respondents liked the app. A total of 88% of participants reported that it was easy to fit the exercises into their daily routine, and there was over 90% adherence for entering daily step counts. Notably, on day 90 both females and males using Respercise alone demonstrated a 2.22- and 2.27-seconds improvement in time for 5-repetition sit-to-stand tests respectively, above the 1.7 second threshold that is considered clinically meaningful in COPD. Conclusion: Respercise can be successfully deployed in clinical trials, offering the opportunity for standardization of exercise in clinical trials and, with further development, could have wider reach as a home-based intervention for individuals with COPD.

Background Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. Methods sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). Results Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P 1 (P 10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Background:Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publication have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n=1,443), SPIROMICS (n=1,623); ECLIPSE (n=2,349); Pittsburgh COPD SCCOR (n=399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P1 (P < 0.001), and emphysema severity (P10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

[Image: see text] IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key regulator of oxidative stress and cellular repair and can be activated through inhibition of its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (Keap1). Several small molecule disrupters of the Nrf2-Keap1 complex have recently been tested and/or approved for human therapeutic use but lack either potency or selectivity. The main goal of our work was to develop a potent, selective activator of NRF2 as protection against oxidative stress. In human bronchial epithelial cells, our Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one (PSTC), induced Nrf2 nuclear translocation, Nrf2-regulated gene expression, and downstream signaling events, including induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme activity and heme oxygenase-1 protein expression, in an Nrf2-dependent manner. As a marker of subsequent functional activity, PSTC restored oxidant (tert-butyl hydroperoxide)-induced glutathione depletion. The compound's engagement of the Nrf2 signaling pathway translated to an in vivo setting, with induction of Nrf2-regulated gene expression and NQO1 enzyme activity, as well as restoration of oxidant (ozone)-induced glutathione depletion, occurring in the lungs of PSTC-treated rodents. Under disease conditions, PSTC engaged its target, inducing the expression of Nrf2-regulated genes in human bronchial epithelial cells derived from patients with chronic obstructive pulmonary disease, as well as in the lungs of cigarette smoke-exposed mice. Subsequent to the latter, a dose-dependent inhibition of cigarette smoke-induced pulmonary inflammation was observed. Finally, in contrast with bardoxolone methyl and sulforaphane, PSTC did not inhibit interleukin-1β-induced nuclear factor-κB translocation or insulin-induced S6 phosphorylation in human cells, emphasizing the on-target activity of this compound. In summary, we characterize a potent, selective Nrf2 activator that offers protection against pulmonary oxidative stress in several cellular and in vivo models.

CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC50) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca2+-mobilization assays, with a KB (the concentration of antagonist that binds 50% of the receptor population) of 6.5 nM and antagonist potency (pA2) of 8.44, and is fully reversible in washout experiments over 180 minutes. In rat and human whole-blood studies assessing neutrophil activation by surface CD11b expression following CXCL2 (rat) or CXCL1 (human) challenge, danirixin blocks the CD11b upregulation with pIC50s of 6.05 and 6.3, respectively. Danirixin dosed orally also blocked the influx of neutrophils into the lung in vivo in rats following aerosol lipopolysaccharide or ozone challenge, with median effective doses (ED50s) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states in which neutrophils are increased in response to inflammation, such as pulmonary diseases. In comparison with navarixin, a CXCR2 antagonist from a different chemical class, the binding characterization of danirixin is distinct. These observations may offer insight into the previously observed clinical differences in induction of neutropenia between these compounds.

Approximately one-third of patients with chronic obstructive pulmonary disease (COPD) have chronic mucus hypersecretion (CMH) [1], often referred to as chronic bronchitis. Despite treatment with inhaled medications and other therapies such as expectorants or methylxanthines, patients with CMH may continue to experience exacerbations, substantial symptom burden and poor health status [1]. CXCR2 antagonists are effective in multiple preclinical and human models of airway inflammation [2–5]. Danirixin is a competitive, reversible oral CXCR2 antagonist that has been well-tolerated in healthy subjects and in patients with influenza [6, 7]. We report the results of a 52-week Phase 2 study conducted in Germany and the USA (GSK protocol 200163; ClinicalTrials.gov identifier [NCT02130193][1]) assessing the effects of danirixin when added to standard-of-care inhaled medications in participants with symptomatic COPD. Participants with an FEV1≥50% of predicted normal and a history of two exacerbations in the prior 12 months, or one exacerbation and elevated plasma fibrinogen ≥3 mg·mL−1, as well as a history of chronic cough and/or mucus hypersecretion on most days for at least the previous 3 months prior screening, were eligible. Full inclusion and exclusion criteria are available online at clinicaltrials.gov. The study was approved by the Western Institutional Review Board (Puyallup, WA, USA) and the Ethikkommission I, Arztekammer Schleswig-Holstein (Bad Segeberg, Germany). Written informed consent was obtained from all participants. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Lazaar is an employee of GlaxoSmithKline and holds stock in the company. Conflict of interest: Dr. Miller reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Yonchuk reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Leidy reports other from Evidera, during the conduct of the study; other from Evidera, outside the submitted work. Conflict of interest: Dr. Ambery reports other from GSK, during the conduct of the study. Conflict of interest: Dr. Bloomer reports personal fees and other from GSK, during the conduct of the study. Conflict of interest: Dr. Watz reports personal fees from GSK, during the conduct of the study. Conflict of interest: Ms. Tabberer is an employee of and holds stock in GSK. Conflict of interest: Dr. Tal-Singer reports personal fees and other from GSK, during the conduct of the study. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02130193&atom=%2Ferj%2Fearly%2F2018%2F08%2F16%2F13993003.01020-2018.atom

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease that has been traditionally characterized by incompletely reversible airflow limitation. Yet, the latter is poorly correlated with many other clinically relevant characteristics of the disease. Thus, the identification of biomarkers to more accurately assess this heterogeneity and disease severity may facilitate the discovery and development of new treatments and better management of patients with COPD. One molecule that has attracted attention as a potentially useful biomarker specifically for the emphysema subpopulation is the soluble receptor for advanced glycation end products (sRAGE). As the soluble isoform of a key proinflammatory signaling receptor, sRAGE acts as a "decoy" for RAGE ligands and prevents their interaction with the receptor. Multiple reports have now linked sRAGE to COPD, and more specifically to emphysema, and evidence is accumulating that this link is likely mechanistic in nature. Here we review the current state of knowledge about sRAGE biology, the mechanistic links to COPD, and the evidence for using it as a biomarker for emphysema. We also discuss sRAGE as a potential target for therapeutic intervention in COPD.