Current Drug Targets (v.12, #4)

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airflow limitation and abnormal inflammatory response of the lungs to exogenous stimuli such as particles and gasses, primarily cigarette smoke [1]. COPD management is based mainly on smoking cessation, bronchodilator therapy and antinflammatory treatment such as steroids, prompt treatment of exacerbations and support of ventilation by invasive or non invasive modalities. However, effective definitive treatment of the disease does not exist despite therapeutic advances. Management of advanced COPD may be challenging; patients with severe forms of the disease or, those patients who experience severe exacerbations, may present critical deterioration requiring management in the Intensive Care Unit (ICU) [2]. COPD is still associated with significant morbidity and mortality and the disease is expected to be the third leading cause of death by 2020 [1]. In this respect, understanding the pathophysiology of the disease and development of effective novel therapeutic strategies are mandatory. COPD is marked by an excessive accumulation of cytokines and inflammatory cells which is further amplified in the severe forms of the disease and during exacerbations. The role of macrophages and lymphocytes at stable disease and at exacerbations has been already pointed out [3, 4]. These phenomena might partially explain the increased and prolonged inflammation seen at COPD. In addition, previous studies [5] provided evidence for the role of immunomodulation in COPD studying the role of dendritic cells whose primary function is the activation of T lymphocytes and the induction of primary immune responses suggesting an immune component in the pathophysiology of the disease. Tsoumakidou et al. [6] reviewed mechanisms implicated in innate and adaptive immune responses which are critical components of the host defence against exogenous stimuli and therefore, essential for COPD pathogenesis. Furthermore, there is evidence that in COPD, mechanisms controlling apoptosis of epithelial and inflammatory cells in the lungs may be altered. This is supported by a number of studies that reported increased induction of apoptosis in the inflammatory milieu of the airway in COPD patients [7-9]. In this respect, the role of defects in the apoptotic processes, such as failed efferocytosis, may be a promising field for the establishment of new therapies that are directed towards COPD specific pathology [10]. Especially in COPD patients, apoptotic processes are accelerated in the lung areas with excessive oxidative stress [7]. In turn, increased oxidative stress in the lungs has been related to increased expression of pro-inflammatory mediators, downregulation of relevant anti-inflammatory genes, increased sequestration of neutrophils in the pulmonary microvasculature, inactivation of antiproteinases, epithelial injury and mucus hypersecretion [11]. The sources of the increased oxidative stress in COPD derive either from inhaled oxidants or/and from the increased amounts of reactive oxygen species, generated by inflammatory and structural cells involved in the pathophysiology of the disease and can be triggered at exacerbations by exogenous stimuli such as bacteria [12]. Loukides et al. [11] reviewed several mechanisms of oxidative stress which are potentially related to COPD pathogenesis and highlighted pathways with potential therapeutic implications in COPD. Special Issues in Critically ill COPD Patients The development of novel efficient therapies for critically ill COPD patients requires not only understanding of the underlying pathobiology but also management of specific problems that critically ill COPD patients may present. First, these patients present immune defect due to the nutritional depletion which is associated with critical illness [13]. Chronic COPD undernutrition and acute micronutrient deficiency in ICU may compromise cytokine response and affect immune cell trafficking. The combination of undernutrition and infection may further weaken the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators [14]. Thus, the immune response to exogenous insult such as bacteria colonizing the airway lumen may be insufficient, resulting in serious infections. Consequently, airway colonization caused by multidrug resistant bacteria may be critical for subsequent airway and lung parenchymal infections and may affect inversely the outcome of critically ill COPD patients [2, 15]. Gram negative bacteria which often colonize or infect the airways, such as pseudomonas aeruginosa strains, may show high frequencies of mutations in the environment of increased oxidative stress - which characterizes COPD - and this might be involved in the development of resistance to antibiotics [16-18]. In this respect, thorough understanding of pathogenetic mechanisms for airway colonization and of the mechanisms underlying bacterial (especially ps. areoginosa) resistance is a priority for effective management of severe COPD patients [15, 16]. Another important problem in critically ill COPD patients is muscle function impairment. This might be due to undernutrition and muscle wasting but also due to the fact that respiratory muscles are subject to the same systemic inflammatory, oxidative and metabolic insults as limb muscles, both in stable COPD and during acute exacerbations. Thus, critically ill COPD patients may often require mechanical support of breathing. This may entrap patients into a viscous circle since the use of mechanical ventilation may induce further respiratory muscle wasting and lung function deterioration. Notably, it has been reported that mechanical ventilation may affect inflammatory pathways known to be activated on stretch, in several experimental conditions of ventilation [19]. In this issue, Klimathianaki et al. [20] review muscular and cellular adaptive responses to the increased ventilatory load that characterizes COPD. Apart from the pathologic changes in airways and parenchyma, pulmonary circulation can be also affected in COPD and pulmonary hypertension is not rare in COPD. Several growth factors, including vascular endothelial and fibroblast factor are strongly expressed in pulmonary vascular endothelium of patients with pulmonary hypertension secondary to hypoxic conditions; Endothelin-1 levels were found increased in exacerbations implying a role in the pulmonary hypertension secondary to COPD. Thus, pathways of vascular remodelling and of pulmonary hypertension are potential drug targets which might be useful in COPD patients with severe PH, such as and#x201C;out of proportion PHand#x201D; where management is challenging for physicians [21]. This special issue of the Current Drug Targets reviews recent advances in COPD pathobiology (cell immune response, oxidative stress and apoptosis) [6, 10, 11] and focuses on problems related to severe disease such as respiratory muscle dysfunction [20], nutrional depletion [14], pulmonary hypertension [21] and airway colonization by bacteria resistant to antibiotics [15, 16] which could be targets for novel therapies in the future.

Mechanisms of Altered Cell Immunity and Cytotoxicity in COPD by M. Tsoumakidou, I. Tsiligianni, N. Tzanakis (450-459).
The lungs of smokers are exposed to the toxic substances of cigarette smoke, but only 10-20and#x25; of them will develop chronic obstructive pulmonary disease (COPD). For COPD to develop, cigarette smoke has to bypass or overwhelm the host front lines of defence, i.e. the respiratory tract mucosal epithelium, which serves as an effective physical barrier and the innate immune system, which provides an immediate, yet non-specific response. In this review, we will describe briefly how cigarette smoke succeeds in damaging the physical barrier of mucosal epithelium and the innate immune system, and how it induces effector mechanisms of the adaptive immune system, which are particularly cytotoxic to the host. We will also discuss the role of other stimuli with immunogenic potential, such role of pathogens which colonize or evade the lungs of COPD patients and of self tissue antigens, which may lead to autoimmune disease when there is chronic inflammation. Although the primary mechanism(s) of undesirable innate and adaptive immune responses in COPD are still a matter of debate, it is currently accepted that they are the root cause of COPD.

Airway Clearance of Apoptotic Cells in COPD by Violet R.S. Mukaro, Sandra Hodge (460-468).
Apoptosis of bronchial epithelial cells and the phagocytic clearance of these cells by alveolar macrophages (a process termed efferocytosis) are integral processes leading to repair of airway epithelial injury. Efferocytosis allows for the removal of apoptotic material with minimal inflammation and prevents the development of secondary necrosis and ongoing inflammation. Defective efferocytosis and the increased presence of apoptotic cells have been identified in the airways of subjects with chronic obstructive pulmonary disease (COPD). There are three major potential causes for this accumulation of apoptotic cells: (i) increased apoptosis per se as a result of an increase in apoptotic mediators, (ii) defects in the recognition of apoptotic cells by AM and (iii) failure to clear the unwanted cells by the process of efferocytosis. The implications of these processes in COPD and novel treatment strategies aimed at improving clearance of apoptotic cells form the focus of the present review.

Oxidative Stress in Patients with COPD by Stelios Loukides, Petros Bakakos, Konstantinos Kostikas (469-477).
The lung is the organ with the highest exposure to ambient air in the entire human architecture. Due to its large surface area and blood supply, the lung is susceptible to oxidative injury in the form of myriads of reactive oxygen species (ROS) and free radicals. In order to provide defense against the oxidative burden, the lungs produce various endogenous agents called antioxidants. The antioxidant species help the lungs ward off the deleterious consequences of a wide variety of oxidants/ROS, either of endogenous or environmental origin. Several mechanisms are related to the potential connection between COPD and oxidative stress. One of the most important actions of the oxidative stress is the influence of the molecular mechanisms involved in the expression proinflammatory genes. There is plenty of evidence supporting an imbalance between oxidants and antioxidants in the lung and systemic circulation of smokers and COPD patients. Detection of the oxidative burden and evaluation of their progression and phenotypes by oxidative stress biomarkers have proven challenging and difficult. Both invasive and noninvasive techniques have provided different biomarkers which contribute to the oxidative burden of the airways. An effective wide-spectrum antioxidant therapy with bioavailability is urgently needed to control the local and systemic oxidative burst in COPD. In that direction, several antioxidant agents have been evaluated as potential candidates for the management of COPD. However, despite some encouraging results, clinical trials so far have failed to elaborately define the type of antioxidant, the regimen and the time period of treatment that may improve clinically meaningful outcomes in patients with COPD.

Respiratory Muscle Dysfunction in COPD: From Muscle to Cell by M. Klimathianaki, K. Vaporidi, D. Georgopoulos (478-488).
Respiratory muscle dysfunction is a cardinal feature of acute and chronic respiratory failure in COPD. Diaphragm and accessory inspiratory muscles face increased load due to increased lung resistance and elastance, as well as increased ventilatory demands. Concomitantly, the capacity of the inspiratory muscles to generate pressure is decreased due to mechanical disadvantage imposed by hyperinflation. Additionally, inflammation and oxidative stress impair muscle fiber specific force generation and increase diaphragm susceptibility to sarcomere disruption during acute inspiratory loading. In response to this increased load, diaphragm presents unique adaptations in its cellular structure and passive and contractile mechanical properties, and displays a more efficient metabolic armamentarium. A shift of muscle fiber type towards slow-twitch, oxidative type I fibers, which are more fatigue-resistant, increases diaphragmatic endurance but protein degradation and a significant reduction in myosin content decrease its force generating capacity. Furthermore, diaphragm adapts to chronic hyperinflation by sarcomere deletion so that its overall length is shortened, in an attempt to preserve optimum force-length relationship. Adaptation however may not be complete, or may be overwhelmed by pathophysiologic derangements during exercise or acute exacerbations, leading to obvious and#x201C;dysfunctionand#x201D; of the respiratory muscles, and if sustained, ultimately to muscle fatigue and respiratory pump failure.

Immunologic Impact of Nutrient Depletion in Chronic Obstructive Pulmonary Disease by Ronit Herzog, Susanna Cunningham-Rundles (489-500).
Chronic obstructive pulmonary disease (COPD) is characterized by small airways, alveolar and systemic inflammation and remodeling causing airflow limitation and parenchymal destruction. Mechanisms of oxidative stress include exposure to cigarette smoke and environmental stimuli that activate proinflammatory responses, stimulate alveolar neutrophils and macrophages and lead to apoptosis of endothelial and epithelial cells. COPD may have origins in fetal and neonatal factors that affect intrauterine growth of lungs and airways, lead to low birth weight and impair the development of immune response. Maternal smoking may diminish interferon response secondary to micronutrient deficiency, particularly of Vitamin A, and support persistence of Respiratory Syncytial Virus (RSV), normally a childhood pathogen, into adult life. Muscle wasting and cachexia are systemic features of COPD. Cachexia is associated with systemic inflammation and worsened by Vitamin D deficiency. Nutritional depletion is related to poor survival and is a rational target for therapeutic intervention in advanced and critically ill patients. Preliminary studies suggest that supplementation with omega-3 polyunsaturated fatty acids and micronutrient repletion with Vitamin A, Vitamin D3, and zinc may have beneficial effects in COPD.

Pulmonary Hypertension in COPD: Pathophysiology and Therapeutic Targets by E. Zakynthinos, Z. Daniil, J. Papanikolaou, D. Makris (501-513).
The incidence of mild to moderate pulmonary hypertension (PH) is highly prevalent, reaching to 50and#x25; in advanced chronic obstructive pulmonary disease (COPD). However, a subpopulation (1-4and#x25; in most studies) with grim prognosis despite moderate airflow limitation, present with and#x201C;out-of-proportionand#x201D; severe PH, as arbitrarily defined by a mean PHand#x2265;40 mmHg, at rest. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating (nitric oxide, prostacyclin) and vasoconstrictive agents (endothelin-1) and imbalance among them. PH in COPD is caused by vasoconstriction and remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. Hypoxia, inflammation and toxic effects of cigarette smoke, independently or additively interacting, are confirmed factors leading to PH. To date, longterm supplemental oxygen remains the primary treatment in COPD patients with PH. The administration of new vasodilators (prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors) dedicated to idiopathic pulmonary arterial hypertension in the disproportionate subgroup of patients with and#x201C;out-of-proportionand#x201D; PH may be considered in the setting of clinical trials. The use of these drugs in COPD patients with PH andlt; 40 mmHg may worsen gas exchange, and to date, has no proven benefit. Future treatments must target more directly pathogenetic mechanisms. Therefore, novel agents have been proposed and are under active investigation, including 5-HT receptor antagonists, Rhokinase inhibitors, statins and stem cell therapy.

Pathophysiology of Airway Colonization in Critically ill COPD Patient by Saad Nseir, Florence Ader, Remy Lubret, Charles-Hugo Marquette (514-520).
Although noninvasive ventilation (NIV) use in severe acute exacerbation of COPD has substantially reduced the need for intubation, an important number of COPD patients still are mechanically ventilated through a tracheal tube in the ICU. Intubation is a major risk factor for lower respiratory tract colonization (LRTC) in ICU patients. Other risk factors for LRTC include colonization of the oral cavity, nasopharynx, and gastric content. Aspiration of contaminated oropharyngeal secretions is increased by supine position, underinflation of tracheal cuff, coma, and sedation. Tracheal tube biofilm formation plays an important role as a reservoir for microorganisms. Reduced cough reflex, altered mucocilliary clearance, hypersecretion and retention of mucus are frequent in COPD patients. In addition, malnutrition and corticosteroid use are common in this population resulting in altered cellular, and humoral immunity and higher risk for LRTC. Incidence of LRTC varies from 22-95and#x25; of intubated patients. Pseudomonas aeruginosa is the most frequently isolated microorganism at day 3 after intubation in COPD patients. LRTC is a major risk factor for ventilator-associated pneumonia, which is associated with increased mortality and morbidity in ICU patients. Several measures could be suggested to reduce LRTC in critically ill COPD patients. NIV use in severe acute exacerbations reduces the need for intubation. In addition, the early use of NIV averts respiratory failure after extubation and could reduce the duration of invasive mechanical ventilation. Other measures might be efficient in preventing LRTC such as semirecumbent position, avoidance of gastric distension, polyurethane-cuffed tracheal tubes, silver-coated tracheal tubes, subglottic aspiration, and continuous control of cuff pressure. Further studies should determine the impact of preventive measures aiming at preventing LRTC on outcome of COPD patients requiring intubation and mechanical ventilation in the ICU.

Mechanisms of Bacterial Resistance to Antibiotics in Infections of COPD Patients by Jennelle M. Kyd, John McGrath, Ajay Krishnamurthy (521-530).
A key characteristic of airway inflammation in chronic obstructive pulmonary disease (COPD) is the persistent presence of bacteria in the lower airways. The most commonly isolated bacteria in the lower respiratory tract of COPD patients are nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae, with growing evidence of the significance of Pseudomonas aeruginosa infections in severe COPD disease. This review focuses on the antibiotic resistant mechanisms associated with the gram-negative bacteria H. influenzae and M. catarrhalis and comparison with P. aeruginosa infection because of the recent evidence of its significance in patients with severe COPD disease. These mechanisms of resistance to and#946;-lactams in H. influenzae and M. catarrhalis are mostly associated with serine and#946;-lactamases of class A type, whereas P. aeruginosa strains exhibit a much broader repertoire with class A-D type mechanisms. Other mechanisms of antibiotic resistance include membrane permeability, efflux pump systems and mutations in antimicrobial targets. Antimicrobial resistance within biofilm matrices appears to be different to the mechanisms observed when the bacteria are in the planktonic state. P. aeruginosa exhibits a more numerous and diverse range of antimicrobial resistance mechanisms in comparison to M. catarrhalis and H. influenzae. The recognition that P. aeruginosa is associated with exacerbations in patients with more severe COPD and that turnover in infecting strains is detected (unlike in cystic fibrosis patients), then further investigation is required to better understand the contribution of antimicrobial resistance and other virulence mechanisms to poor clinical outcomes to improve therapeutic approaches.

Mechanism of Bioactive Transfer through Liposomal Bilayers by Behnoush Maherani, Elmira Arab-Tehrany, Michel Linder (531-545).
Today, liposomes are one of the most effective carrier systems employed in biological, pharmaceutical, medical and nutritional research. In order to optimize a liposomal formulation for the encapsulation, delivery and release of the entrapped material, it is necessary to study material passage through the lipidic and aqueous phases of the lipid vesicle. Towards this end, this article aims to review the mechanisms of bioactive transfer between different layers of a liposome and it also discusses the bioactive release mechanism. Several methods of detection and observation of bioactive transfer in liposomal systems are presented.

The Use of Structural Biology in Janus Kinase Targeted Drug Discovery by Nilda L. Alicea-Velazquez, Titus J. Boggon (546-555).
The Janus kinases (or Jak kinases) mediate cytokine and growth factor signal transduction. Acquired or inherited Jak mutations can result in dysregulation of Jak-mediated signal transduction and can be critical to disease acquisition in neoplasias including acute myeloid, acute lymphoblastic and acute megakaryoblastic leukemias, and in rare X-linked severe combined immunodeficiency. The discovery of an acquired Jak2 point mutation, V617F, in significant numbers of patients with classical myeloproliferative disorders has increased the interest in development of Jak2-specific tyrosine kinase inhibitors and consequently there are now over 20 publically available structures of Jak kinase domains that describe all four family members, Jak1, Jak2, Jak3, and Tyk2. Here we review the recent advances in understanding the druggable structure and function of the Jak family, with a focus on the structural biology of the Jak kinase domain. We will discuss how these advances impact the development of Jak-targeted therapeutics.

The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival by Arash S. Saffar, Heather Ashdown, Abdelilah S. Gounni (556-562).
Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.

Dasatinib: An Anti-Tumour Agent via Src Inhibition by Antonio Gnoni, Ilaria Marech, Nicola Silvestris, Angelo Vacca, Vito Lorusso (563-578).
Dasatinib (BMS-354825, Spryceland#174;) is an oral, multitargeted inhibitor of receptor tyrosine kinases (RTKs), including BCR-ABL fusion protein, stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGFR), and Src family kinases (SFKs). Several early- and late-phase clinical trials for chronic myelogeneous leukaemia (CML) have demonstrated the direct inhibition of BCR-ABL fusion protein and SFKs, which led to dasatinib approval by the Food and Drug Administration (FDA) and the European Union for the treatment of imatinib-resistant or -intolerant CML, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Phase III dose-optimization study was performed to compare different regimens, stating that dasatinib 100 mg once daily is now the recommended schedule for patients with chronic CML, and 140 mg once daily for patients with accelerated phase or myeloid or lymphoid blast phase CML, and for patients with Ph+ ALL until progression. Because of the myriad of critical roles of SFKs in biological processes, SFKs inhibition could induce numerous biological responses. Ongoing clinical trials evaluate dasatinib in the treatment of several solid tumours, including gastrointestinal stromal tumours (GIST), prostate cancer, malignant pleural mesothelioma, sarcomas, NSCLC, colorectal cancer, glioblastoma and other haematologic malignances as multiple myeloma. Ongoing pre-clinical studies assess the therapeutic potential of dasatinib in other solid tumours, including melanoma, head and neck cancer, breast cancer and ovarian cancer. Dasatinib is generally well tolerated. Myelosuppression is the common adverse event which is, however, reversible by dose reduction, discontinuation, or interruption. Thrombocytopenia is more significant than neutropenia and associated to gastrointestinal bleeding and CNS haemorrhage. The most common non-haematologic adverse events include gastrointestinal symptoms (diarrhoea, nausea, vomiting, abdominal pain and anorexia), headache, peripheral edema, and pleural effusion. In respect of these encouraging studies investigating dasatinib in the treatment of patients with GIST, prostate cancer, multiple myeloma and sarcomas, ongoing phase III clinical trials warrant the drug evaluation as recommended agent for the treatment of these diseases, also in association with chemotherapy or other targeted therapies.

Colloidal Carrier Systems for Transcutaneous Immunization by Prem N. Gupta, Suresh P. Vyas (579-597).
Recently, the skin has emerged as a potential alternative route for non-invasive delivery of vaccine. It has been recognized as a highly immune-reactive tissue containing an abundance of antigen presenting cells, especially within the epidermis. Transcutaneous immunization, introduction of antigen through topical application onto the intact skin, has many practical merits compared to injectable routes of administration. It combines the advantages of needle-free delivery while targeting the immunologically rich milieu of the skin. This simple and non-invasive immunization procedure elicits systemic and cell mediated immune responses and therefore, it provides a viable and cost-effective strategy for disease prevention. Various strategies i.e physical, chemical and novel carrier systems can be explored for trancutaneous immunization. Specially designed vaccine carrier systems are attracting immense attention and these could be potential module for non-invasive antigen delivery. The review covers topical delivery consideration in brief followed by an insight into various novel delivery systems for transcutaneous vaccine delivery.