Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660).

Aims: Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study.

Methods: Single escalating oral doses of GSK2793660 from 0.

Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2.

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 (pIC) of 7.

Mechanisms of Vascular Dysfunction in COPD and Effects of a Novel Soluble Epoxide Hydrolase Inhibitor in Smokers.

Background: Smoking and COPD are risk factors for cardiovascular disease, and the pathogenesis may involve endothelial dysfunction. We tested the hypothesis that endothelium-derived epoxyeicosatrienoic acid (EET)-mediated endothelial function is impaired in patients with COPD and that a novel soluble epoxide hydrolase inhibitor, GSK2256294, attenuates EET-mediated endothelial dysfunction in human resistance vessels both in vitro and in vivo.

Methods: Endogenous and stimulated endothelial release of EETs was assessed in 12 patients with COPD, 11 overweight smokers, and two matched control groups, using forearm plethysmography with intraarterial infusions of fluconazole, bradykinin, and the combination.

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor.

Aims: Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies.

Methods: Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers.

Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung.

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.

A diVIsive Shuffling Approach (VIStA) for gene expression analysis to identify subtypes in Chronic Obstructive Pulmonary Disease.

Background: An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions.

Results: We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns.

The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study.

Background: Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density.

Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease.

Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost.

Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics.

Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study.

In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor.

Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration.

Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis.

Lung pathology in cystic fibrosis is linked to dehydration of the airways epithelial surface which in part results from inappropriately raised sodium reabsorption through the epithelial sodium channel (ENaC). To identify a small-interfering RNA (siRNA) which selectively inhibits ENaC expression, chemically modified 21-mer siRNAs targeting human ENaCα were designed and screened. GSK2225745, was identified as a potent inhibitor of ENaCα mRNA (EC(50) (half maximal effective concentration) = 0.

Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype.

Background: Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).

Methods And Findings: Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years.

Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage.

Macrophages release cytokines that may contribute to the chronic inflammation observed in pulmonary conditions such as asthma and chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have a therapeutic benefit. Human lung macrophages are a rich source of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-8, that are elevated in the bronchoalveolar lavage and sputum of subjects with respiratory diseases.

The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke.

Objectives: In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated.

Methods: Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12).

Structure-activity relationship of hydroxamate-based inhibitors on the secretases that cleave the amyloid precursor protein, angiotensin converting enzyme, CD23, and pro-tumor necrosis factor-alpha.

Multiple proteins are proteolytically shed from the membrane, including the amyloid precursor protein (APP) involved in Alzheimer's disease, the blood pressure regulating angiotensin converting enzyme (ACE), the low affinity IgE receptor CD23, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The inhibitory effect of a range of hydroxamic acid-based compounds on the secretases involved in cleaving and releasing these four proteins has been examined to build up a structure-activity relationship. Compounds have been identified that can discriminate between TNF-alpha convertase and the other three secretases (compound 15), between the shedding of CD23 and the shedding of APP and ACE (compound 21), and between the secretases and matrix metalloproteinase-1 (compound 22).