Current Drug Targets (v.14, #2)

Editorial (Hot Topic: COPD Management Beyond Bronchodilation: Current Targets and Future Prospects) by Konstantinos Kostikas, Petros Bakakos, Stelios Loukides (139-140).

Immune and Genetic Mechanisms in COPD: Possible Targets for Therapeutic Interventions by Eleni G. Tzortzaki, Alberto Papi, Eirini Neofytou, Nikolaos Soulitzis, Nikolaos M. Siafakas (141-148).
Genetic, immune and environmental interactions are key elements for the development of COPD. Cigarette smoking is considered the primary risk factor initiating inflammatory cascades in genetically susceptible individuals. The “danger signals” elicited by the injured cells of non-specific immunity induce the downstream activation of proinflammatory cascades and antigen-specific adaptive immune responses. The produced oxidative stress further damages the lung leading to acquired genetic changes (histone deacetylation, microsatellite DNA instability, DNA methylation, telomere shortening, miRNA alterations) due to an inefficient DNA repair machinery. On the other hand, augmented apoptosis, impaired efferocytosis and abnormal tissue remodeling contribute to the chronic inflammatory response and tissue destruction in COPD. This review focuses on the role of genetic, epigenetic and immune mechanisms in the development of COPD in order to put forward possible prognostic and therapeutic targets.

Can We Delay the Accelerated Lung Aging in COPD? Anti-Aging Molecules and Interventions by Andriana I. Papaioannou, Christos Rossios, Konstantinos Kostikas, Kazuhiro Ito (149-157).
Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging. The prevalence of COPD is age-dependent suggesting an intimate relationship between the pathogenesis of COPD and aging. Lung function decline, the hallmark feature of COPD evolution, is more prominent with increasing age and this decline is greater in smoking individuals. One of the major goals of COPD pharmacotherapy is the development of drugs that would be able to result in a decrease of the decline in lung function over years. However, till nowadays smoking cessation is the only known intervention which is able to decelerate lung function decline. Several mechanisms of aging, including oxidative stress, inflammation and telomere shortening have been shown to be implicated in COPD. Furthermore, numerous anti-aging molecules, including sirtuins and Nrf-2 are reduced, and pathways such as mTOR and genes such as Klotho have also been shown to be abnormal in the lungs of COPD patients. The above mechanisms have been associated with the accelerated lung aging in COPD patients. Numerous therapeutic interventions have been studied in an attempt to reverse accelerated lung aging, and some of them have already been tested in clinical trials. The aim of the present review is to summarize the mechanisms associated with the accelerated lung aging in COPD and to provide information about the possible therapeutic implications targeting those mechanisms.

Managing Comorbidity in COPD: A Difficult Task by Ioanna G. Tsiligianni, Epameinondas Kosmas, Thys Van der Molen, Nikolaos Tzanakis (158-176).
Chronic obstructive pulmonary disease is a public health problem that results in high morbidity, disability and mortality. Comorbidities are highly prevalent in COPD patients because of aging, common risk factors and pathways, rising mortality, and disability. In this review article we present the most prevalent co-morbidities in COPD patients, we face the issue of multimorbidity and discuss the practical management approach relevant to chest physicians and general practitioners. Issues on comorbidities management according to general guidelines as well as their implications for COPD are raised. The aim is to give clinicians an easy update with specific recommendations for each comorbidity. The implications of several medications used for comorbidities in COPD in terms of benefits, concerns, medication preference, medication avoidance and contraindications are also discussed.

Systemic Biomarkers in the Evaluation and Management of COPD Patients: Are We Getting Closer to Clinical Application? by Konstantinos Kostikas, Petros Bakakos, Spyros Papiris, Daiana Stolz, Bartolome R. Celli (177-191).
Chronic obstructive pulmonary disease (COPD) is a complex, multicomponent disease at the clinical, cellular, and molecular levels. Over the past few years there has been a growing interest in the field of biomarkers in COPD and a large number of studies have evaluated potential candidate molecules in different patient settings. Data on systemic biomarkers from large cohorts, including the well-characterized population of the ECLIPSE study, are now available and provide exciting information on the association of biomarkers with clinically important outcomes, including exacerbations, hospitalizations and mortality. Moreover, recent research has provided proof for the existence of distinct "systemic inflammatory" phenotypes. This review summarizes the currently available evidence on systemic biomarkers in COPD, providing clinically relevant information on the possible role of systemic biomarkers in the evaluation of disease activity and severity, phenotypes, outcomes, COPD exacerbations and treatment response and guidance. Despite the fact that no single biomarker is currently ready to characterize sufficiently the status of COPD patients, guide treatment options, and predict future events, recent studies have rendered our current knowledge definitely more advanced than a few years ago and the possible use of biomarkers in the diagnosis and management of COPD patients looks even more promising.

Inhaled Corticosteroids in COPD: Pros and Cons by Eleftherios Zervas, Konstantinos Samitas, Mina Gaga, Bianca Beghe, Leonardo M. Fabbri (192-224).
Chronic obstructive pulmonary disease (COPD) is a devastating illness characterized by airway and systemic inflammation, progressive airway obstruction and exacerbations. It is a major cause of chronic morbidity and mortality, projected to be the third leading cause of death by the year 2020. Although there is currently no definite cure, COPD is both a preventable and treatable disease. Important changes in our perspective and understanding of the disease have been made that lead to marked improvements in the treatment of COPD, such as the use of long-acting anticholinergics, β2 agonists and inhaled corticosteroids (ICS). Current GOLD guidelines call for the use of ICS in patients with severe and very severe airflow limitation and/or for patients with frequent exacerbations. This population constitutes only around 20% of all COPD patients, however current data show that as much as 70% are prescribed ICS. Although widely used, clinical trials on the efficacy of ICS in COPD have been up to now inconclusive or even contradictory. This has lead to wide confusion and debate regarding their role in the management of COPD. This review summarizes all current knowledge originating from observational studies, randomized clinical trials and expert views regarding ICS therapy in COPD. Arguments in favor and against the use of ICS are presented with respect to airway and systemic inflammation, exacerbation frequency and severity, lung function decline, quality of life, mortality and adverse events.

Antioxidants and Mucolytics in COPD Management: When (if ever) and in Whom? by Georgios Hillas, Sofia Nikolakopoulou, Sabah Hussain, Theodoros Vassilakopoulos (225-234).
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Oxidative stress is an important mechanism in the pathogenesis of this disease. The oxidant/ antioxidant imbalance occurring in smokers and patients with COPD is well established. Thus, therapeutic strategies targeting oxidative stress with pharmacological antioxidant agents or boosting the endogenous levels of antioxidants is likely to be beneficial as an adjunctive tool in the treatment of COPD patients. Thiol compounts such as N-acetyl-L-cysteine (NAC), carbocysteine, erdosteine, and fudosteine have been extensively studied. Although some results remain controversial, NAC and carbocysteine seem to have beneficial effect in patients not receiving inhaled corticosteroids who suffer from frequent exacerbations. In addition, other antioxidants like superoxide dismutase (SOD) mimetics and nuclear factor-erythroid 2 related factor 2 (Nrf2) are shown to decrease markers of oxidative stress in patients with emphysema, while others like glutathione peroxidase (GPx) mimetics and NO synthase (iNOS) can prevent both inflammation and oxidative stress in clinical trials in vivo (or in mouse models). In this article we review the effectiveness of various antioxidant factors in COPD and their potential beneficial effect in the treatment of the disease.

Novel Anti-Inflammatory Agents in COPD: Targeting Lung and Systemic Inflammation by Stelios Loukides, Konstantinos Bartziokas, Jorgen Vestbo, Dave Singh (235-245).
Inflammation plays a central role in chronic obstructive pulmonary disease (COPD). COPD related inflammation is less responsive to inhaled steroids compared to asthma. There are three major novel anti-inflammatory approaches to the management of COPD. The first approach is phosphodiesterase inhibitors, such as roflumilast which provides additional clinical benefit either as a single agent or as an additive treatment to long-acting bronchodilators. The second approach involves novel strategies using drugs licensed for other indications, such as statins and macrolides; limited prospective studies on these strategies exist at the moment. A third potential approach involves novel agents whose mechanism of action is closely related to COPD mechanisms and pathophysiology. Such novel treatments are of great interest since they may treat both COPD and co-morbidities. Several novel agents are currently under development and may be of importance in the future.

Stem Cell Therapy in Chronic Obstructive Pulmonary Disease. Seeking the Prometheus Effect by Argyris Tzouvelekis, Geoff Laurent, Demosthenes Bouros (246-252).
Chronic obstructive pulmonary disease is characterized by dramatic alterations in lung architecture associated to an exaggerated inflammatory process, alveolar epithelial cell apoptosis, endothelial dysfunction and extracellular matrix destruction due to a protease and anti-protease imbalance. In addition a significant inflammatory spillover into systemic circulation has been suggested to be responsible for a wide range of fatal comorbidities. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will fulfill the unmet need of modulating both local and systemic inflammation and at the same time accelerate alveolar epithelial and endothelial turnover intervening into disease natural course and not only relieving patient's symptoms. Regenerative medicine based on stem cells properties represents one promising option with several fruitful therapeutic applications in patients with COPD. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administrated stem cells within the COPD lung as well as the mechanisms regulating activation of resident progenitor cells. The above evidence coupled with the rather disappointing results emerging from the first stem cell clinical trials in COPD patients underline the need for careful study design by setting realistic goals to assess efficacy such as biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn.

Novel Modalities and Agents in Bronchoscopic Lung Volume Reduction by Grigoris Stratakos, Philip Emmanouil, Stefano Gasparini (253-261).
The NETT study has shown the effectiveness of lung volume reduction surgery (LVRS) in improving functional parameters and exercise tolerance in selected patients with severe pulmonary emphysema of upper lobe predominance. A number of bronchoscopic techniques have since been developed under the term “bronchoscopic lung volume reduction” (BLVR), aiming to lower the complications and the cost while facilitating the procedure of lung volume approach in patients with emphysema. These include airway bypass by creation of airway/parenchyma communications, one-way endobronchial valves occluding the airways of the targeted lobes, endobronchial coils which mechanically contract the parenchyma, hot vapour ablation thermally destroying the targeted sites and sealant which fill the alveoli with polymer material. These methods are generally simple and safe, with a favourable complications profile, requiring less infrastructure and interventional experience than the open surgical approach. Bronchial valves have produced promising results in a very narrow phenotype of emphysema patients and have the major advantage of being reversible in their action. Parenchymal interventions at the cost of producing permanent effects and a transient inflammatory syndrome, may be effective in larger group of patients regardless of the fissure integrity and the presence of collateral ventilation. New, more extensive multicentre studies are underway which aim at better selection and stratification of patients in order to further evaluate the safety and effectiveness of these techniques, before wider use of this revolutionary approach for severe lung emphysema can be advocated.

Effect of Rehabilitative Exercise Training on Peripheral Muscle Remodelling in Patients with COPD: Targeting Beyond the Lungs by Ioannis Nasis, Eleni A. Kortianou, Enrico Clini, Nikolaos G. Koulouris, Ioannis Vogiatzis (262-273).
Locomotor muscle dysfunction and weakness are frequently observed in patients with Chronic Obstructive Pulmonary Disease (COPD). In addition to intolerable sensations of dyspnoea which importantly contribute to exercise limitation, intrinsic muscle abnormalities have also been implicated in inducing leg muscle fatigue/discomfort during exercise in these patients. It is, however, uncertain whether these intrinsic muscle abnormalities are linked to a specific 'myopathy' or they constitute a consequence of the disease. Besides muscle disuse, other factors which may contribute to peripheral muscle dysfunction include systemic inflammation, oxidative and nitrosative stress, chronic hypoxia, corticosteroid use and malnutrition. There is clear evidence that rehabilitative exercise training induces significant skeletal muscle fibre remodelling and improvements in functionality in the absence of changes in lung function. The ultimate purpose of this review is to identify and summarize the results of studies implementing diverse types of exercise training on peripheral muscle fibre phenotypic and genotypic modifications in patients with COPD.