Current Drug Targets - Volume 7, Issue 6, 2006

Chronic obstructive respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease (COPD) are related to potential numerous causes (Fig. 1) and belong to the major growth areas of pharmacology and pharmaceutics and there is a large variety of new compounds currently in development. These new agents include both substances that represent improvements of existing classes of drugs such as corticosteroids or beta 2 receptor agonists and completely new classes of drugs. These new classes have been developed in the past years due to an improved understanding of the complex pathophysiology of obstructive airway diseases and include agonists and antagonists of specific extracellular and intracellular mediators such as cytokines or chemokines. Bronchial asthma displays an important health care problem, as it exerts a tremendous toll on patients, health care providers, and the societies. The substantial increase in the prevalence of obstructive airway diseases in recent decades has generated sizable concern from both domestic and global perspectives. Epidemiologically, the incidence of allergic diseases, including bronchial asthma has increased in developed countries over the past several decades and these diseases comprise a large component of the work of general practices. Also, in the pediatric sector, asthma-like syndromes represent the most frequent cause of hospitalization in children in western countries. The socio-economic effect of these diseases are high and still increasing. In 1996, 17 million US-Americans, with approximately one third of those being children, were affected by bronchial asthma and the economic burden of the disease is increasing in parallel, from an estimated US$6.2 billion in 1990 to US$12.7 billion in 1998 [1]. These costs include direct medical costs (58%) as well as indirect costs (42%) such as school days lost, loss of work, housekeeping and mortality [1]. Initially identified as a new major medical and socio-economic burden in developed countries, the increase in asthma prevalence is now also becoming more evident in rapidly developing countries in the Third World and in emerging Second World countries transiting to First World economic status and. As an example, the prevalence of asthma has increased in Bangalore, India, a city known for its high asthma prevalence, from 9.0% of the pediatric population in 1979 to 29.5% in 1999 [1]. Similar trends are reported from other parts of the Asian region, such as China. Based on prevalence rates at present and projected increases, it can be estimated that the total population of asthmatic patients in China will be around 150 million, including 38 million children, by the year 2013. These epidemiologic findings point to considerable challenges for public health not only in the developed countries, but globally [2]. With regard to the spiraling treatment costs it is currently debated that there should be a substantial realignment of drug development policy in the pharmaceutical industry and parallel shift in the licensing policy by authorities to encourage the development of novel compounds that are effective in halting the progression from acute to chronic forms of obstructive diseases when the diseases first manifest in early childhood [3]. Since corticosteroids are clinically effective, relatively safe, and easy to administer, they remain the gold standard of anti-inflammatory treatment in bronchial asthma. However, inhaled corticosteroids have failed to halt the progression of the asthma epidemic and they are ineffective in the small group of patients with glucocorticoiddependent and -resistant asthma. Chronic obstructive pulmonary disease on the other hand is mainly caused by tobacco smoking. Therefore, with very few exceptions, smoking cessation displays the only causative and effective treatment of COPD. In this respect, the current pharmacological treatment options of COPD have been found to be more or less unsatisfactory, since they do not influence the natural course or disease severity significantly. In COPD patients without concomitant asthma glucocorticoids are scarcely effective. While bronchodilators may improve symptoms and quality of life in COPD patients, they do not significantly influence the natural course of COPD with the exception of tiotropium and only theophylline has been demonstrated to have significant effects on airway inflammation in patients with COPD. It is also important to mention that the pharmacologic treatment options are not curative but current and future approaches may lead to a better long-term control of chronic airway obstruction. In this respect, it is a major aim to develop novel agents that are as effective existing drugs but have less side effects and have a better route of administration [4, 5]. The present theme issue of Current Drug Targets aims to provide a series of reviews that focus on current aspects of respiratory drug development...........

Nanoparticles are at the leading edge of the rapidly developing field of material science in nanotechnology with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used to transport a large number of compounds. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based "molecular" imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology, nanoparticles have the potential to become useful tools as therapeutic and diagnostic tools in the near future.

Corticosteroids produce a marked improvement in clinical parameters in most asthmatic patients; in contrast, corticosteroids have little effect on lung function measurements in patients with chronic obstructive pulmonary disease. By uncovering the reason for this paradox, it should be possible to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic receptor, which is subjected to posttranslational modifications. Receptor phosphorylation may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Other modifications such as nitration/nitrosylation may also affect glucocorticoid receptor function. Oxidative stress due to cigarette smoke may be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription and reduces glucocorticoid receptor-associated repressor functions. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.

Nuclear factor kappa B (NF-kB) regulates the transcription of a wide array of gene products that are involved in the molecular pathobiology of the lung. Three lung cell types, epithelial cells, macrophages and neutrophils, have been shown to be involved in the generation of lung inflammation through signaling mechanisms that are dependent on activation of the NF-kB pathway. The basic molecular biology of the NF-kB activation pathway is well described, and approaches to modify this axis have involved inhibition of various components of the classical activation pathway, including ubiquitination and proteosomal degradation of IkB. Recently, there have been detailed characterizations of molecular mechanisms that involve reversible post-translational modification of RelA, including phosphorylation and acetylation that might be amenable to therapeutic interdiction. Alternately DNA decoy, antisense and siRNA technologies that interfere with NF-kB binding and inhibition of gene expression, respectively, of NF-kB proteins have been employed in experimental settings, but this has not been practically or effectively applied in human disease. A very promising approach, in our view, is inhibition of inhibitory kappa B kinases (IKK) since these appear to be highly specific for the NF-kB activation pathway and amenable to conventional small molecule pharmaceutical approaches.

Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by recurrent episodes of leukocyte infiltration in the lung parenchyma causing progressive pulmonary tissue damage and loss of function. Recruitment of neutrophils and CD8+ T cells is linked to disease progression and is under control of chemotactic mediators produced in the inflamed COPD lung. Recent progress in elucidation of the molecular mechanisms that regulate migration of inflammatory cells into the lung has revealed interesting novel targets for therapeutic intervention in this disease. Chemokine receptors CXCR1 and CXCR2 expressed on neutrophils and CXCR3 expressed on CD8+ T cells have been identified as potential therapeutic targets to prevent recruitment of pathogenic cells into the inflamed lung. However, the observation that chemokine receptors are also expressed and functional on various types of lung resident cells including epithelial and smooth muscle cells has raised new questions on the role played by chemokine receptors in COPD. These new findings suggest that chemokine receptor signalling could contribute to the adaptive response of lung tissue resident cells to the microenvironmental changes induced by inflammation. Thus, investigation of the role played by chemokine receptors in development of COPD remains a fertile area of research. Nevertheless, validation of chemokine receptor targets in COPD has proven a difficult challenge given the lack of predictive animal models of the disease and the still poorly defined etiology and pathogenesis.

Chronic obstructive pulmonary disease [COPD] is characterised by airflow limitation of peripheral airways that is not fully reversible and progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. There is also intense airway wall remodelling and evidence of systemic inflammation. Increased interleukin [IL]-6, IL-1β, tumor necrosis factor-α [TNF-α], GRO-α, MCP-1 and IL-8 levels are measured in sputum, with further increases during exacerbations. The bronchiolar epithelium over-expresses MCP-1, MIP-1α and IL-8. IL-8 can account for sputum neutrophil chemotactic activity. TNFα and IL-1β stimulate macrophages to produce matrix metalloproteinase- 9 [MMP-9], and bronchial epithelial cells to produce extracellular matrix glycoproteins. Increased expression of transforming growth factor-β [TGFβ) and epidermal growth factor [EGF] occurs in the epithelium and submucosal cells; gene array studies reveal an excess of TGFβ1, CTGF and PDGFRA in COPD. TGFβ and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. Anti-cytokine therapy could be in the form of soluble receptors or by neutralising antibodies, small compounds blocking cytokine receptors or incomplete and non-activating cytokines, inhibitors of protein activation and inhibitors of signal transduction and transcription such as via inhibition of mitogen-activated protein kinases [MAPK] and of transcription factor, nuclear factor κB. Anti-IL-8 therapy has been tried with little effect on COPD, and current trials are on-going with TNF-α inhibitors. Other treatments such as phosphodiesterase 4 inhibitors have anti-cytokine effects that may underlie their beneficial effects in COPD.

Most pathological conditions that result in human diseases are associated with altered gene expression. With the advent of new technologies that might control gene expression and a broader knowledge of transcription factors and pathways, new strategies have emerged that offer promising first results for therapeutical and experimental purposes. This review will focus on different inflammatory conditions of the lung, in which targeting the transduction of involved genes have been successfully attempted.

Allergic asthma is a chronic airway inflammatory disorder attributable to T-helper 2 cell responses together with other inflammatory cells such as mast cells, B cells and eosinophils, and pro-inflammatory cytokines and chemokines. Mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be important in the differentiation, activation, proliferation, degranulation and migration of various immune cells, and airway smooth muscle and epithelial cells. In mammal, MAPK signaling modules are divided into at least 3 groups: extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Each MAPK module plays a discrete yet complementary role in accentuating allergic airway inflammation. Cumulative evidence reveals potential anti-inflammatory activities of MAPK inhibitors in a variety of in vitro models of inflammation. Recently, the anti-inflammatory effects of MAPK kinase inhibitor (U0126), p38 MAPK inhibitors (SB239063 and respirable p38α MAPK antisense oligonucleotide) and JNK inhibitor (SP600125) have been demonstrated in in vivo animal models of asthma. Development of inhibitors targeting at MAPK could be an attractive strategy for the treatment of asthma.

A growing body of evidence has emerged in support of a pro-inflammatory role for adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and COPD. The demonstration that adenosine enhances mast cell allergen-dependent activation, the notion that elevated levels of adenosine are present in chronically inflamed airways, and the results from exposure studies of nebulised adenosine showing dose-dependent bronchoconstriction in subjects with asthma and COPD, emphasise the importance of adenosine in the initiation, persistence and progression in these common inflammatory disorders of the airways. Adenosine exerts its manifold biological activities by interacting with at least four adenosine receptor subtypes. Selective activation or blockade of these sites is being exploited by the pharmaceutical industry in an attempt to generate novel therapies for asthma and COPD. This review article intends to address the potential role of adenosine in asthma and to put forward the idea that drugs that have been developed to selectively activate or downregulate adenosine receptor subtypes may constitute a considerable advance in the management of chronic airway inflammation.

Oxidative stress and chronic inflammation are important features in the pathogenesis of chronic obstructive pulmonary disease (COPD). Oxidative stress has important consequences for several elements of lung physiology and for the pathogenesis of COPD, including oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. Therefore, targeting oxidative stress with antioxidants or boosting the endogenous levels of antioxidants is likely to be beneficial in the treatment of COPD. Antioxidant and/or anti-inflammatory agents such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn), dietary polyphenol (curcumin-diferuloylmethane, a principal component of turmeric), resveratrol (a flavanoid found in red wine), green tea (theophylline and epigallocatechin-3- gallate), ergothioneine (xanthine and peroxynitrite inhibitor), quercetin, erdosteine and carbocysteine lysine salt, have been reported to control NF-kB activation, regulation of glutathione biosynthesis genes, chromatin remodeling and hence inflammatory gene expression. Specific spin traps such as α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), manganese (III) meso-tetrakis (N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150 and AEOL 10113), and a SOD mimetic M40419 have also been reported to inhibit cigarette smoke-induced inflammatory responses in vivo. Since a variety of oxidants, free radicals and aldehydes are implicated in the pathogenesis of COPD it is possible that therapeutic administration of multiple antioxidants will be effective in the treatment of COPD. Various approaches to enhance lung antioxidant capacity and clinical trials of antioxidant compounds in COPD are discussed.

In the respiratory tract, NO is produced by residential and inflammatory cells. NO is generated via oxidation of L-arginine that is catalysed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) are able to modulate bronchomotor tone. NO derived from the inducible isoform of NO synthase, up-regulated by different cytokines via NF-kB-dependent pathway, seems to be a proinflammatory mediator with immunomodulatory effects. The production of NO under oxidative stress conditions secondarily generates strong oxidising agents (reactive nitrogen species) that may amplify the inflammatory response in asthma and COPD. Moreover, NO can be exhaled and levels are abnormal in stable atopic asthma and during exacerbations in both asthma and COPD. Exhaled NO might therefore be a non-invasive tool to monitor the underlying inflammatory process. It is suggested that NOS regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways such as asthma and COPD.

Pulmonary emphysema, a major component of chronic obstructive pulmonary diseases, is a highly prevalent progressive tissue-destructive disease, with no effective treatments. The interplay between inflammation, matrix proteolysis, oxidative stress and apoptosis might account for the irreversible progression of the disease. Recent investigations have underlined the importance of the lung vasculature in the pathobiology of chronic obstructive pulmonary diseases offering new therapeutic strategies. This review will focus on the pulmonary microvessels as a target in the treatment of pulmonary emphysema.

A large number of studies have implicated activation of innate immune mechanisms in the pathogenesis of chronic obstructive pulmonary disease (COPD). Accumulation of inflammatory cells, chemokines and pro-inflammatory cytokines is a hallmark of activation of these mechanisms, but only a few studies have focussed on antimicrobial peptides in COPD. These peptides are a central component of innate immunity, and airway epithelial cells and neutrophils in the lung are the main cellular sources. In addition to their direct antimicrobial action, antimicrobial peptides have been shown to display a variety of activities that may implicate them in the pathogenesis of COPD. This is based on the observation that they not only contribute to defense against respiratory pathogens that have been associated with COPD, but may also contribute to the influx of inflammatory cells, activation of adaptive immunity and epithelial remodeling. The aim of this review is to provide an update on the basic biology of antimicrobial peptides in the lung, with a focus on their putative role in COPD. In addition, the implication of this knowledge for future treatment of COPD is discussed.

Proteases play an essential role in modulating the turnover of extracellular matrix. Furthermore, they are involved in the processing of various proteins thus regulating fundamental cellular functions such as apoptosis, cells growth and activation, protein secretion and phagocytosis. At the tissue and organ levels, proteases influence mechanisms including cell migration and invasion, cellular interactions and signal transduction as well as tissue formation and stabilization. Proteases are classified based on their catalytic mechanisms into serin, aspartic, metallo, threonin and cysteine proteases and are localized extracellularly, at the cellular surface, in the cytoplasm of cells or within specific subcellular structures such as lysosomes. The present review focuses on the specific functions of lysosomal cysteine proteases and the potential effects of modulators of cysteine protease activity.

Leptin seems to regulate various physiological mechanisms besides body weight. Leptin plays a role in vascular biology and pathology as well as renal function. In addition, leptin has been implicated in the regulation of fertility and reproduction. The effect of pharmaceutical agents on circulating plasma leptin levels has been assessed. Among the drugs investigated are glitazones, statins, fibrates, serotonin reuptake inhibitors and cannabinoid-1 receptor antagonists. Since these agents are used to treat pathological conditions there is a potential role for leptin in these states. The degree of involvement of leptin in several pathophysiological states needs to be defined to aid in the development of potentially useful therapeutic agents.

Histone deacetylase inhibitors are nowadays considered as promising anti-cancer drugs, as they interfere with several key steps of tumor development and progression, both in vitro and in vivo. Less attention has been paid to their impact on cell junctions. Nevertheless, cell junctions are gatekeepers in the management of tissue homeostasis, and their aberrant expression and functioning is observed in all aspects of cancer biology. The present review provides a state of the art of the current knowledge concerning the effects of histone deacetylase inhibitors on cell junctions. Besides an updated theoretical basis, we also exemplify its actual relevance in cancer therapy.