Current Drug Targets - Volume 7, Issue 5, 2006

Asthma is a serious international public health problem and is a hot topic in medical research for a number of reasons. Firstly, it is a common disease with the World Health Organization estimating that between 100 million and 150 million people worldwide suffer from the disease. Secondly, it remains an enormous burden on health-care systems, with the economic costs associated with asthma estimated to exceed those of tuberculosis and HIV/AIDS combined. Thirdly, asthma has increased in prevalence over the past two decades in many countries, and this is particularly marked in children. Significant advances in our understanding of the disease have meant several testable hypotheses regarding its etiology and pathogenesis have emerged. Currently, the most widely accepted paradigm is that the most common form of asthma as a multi- phase developmental disease, beginning in childhood as an allergen induced Th-2 mediated inflammation, followed by a consolidation phase in which chronic inflammation induces a self sustaining cycle of airway remodeling and heightened responsiveness that leads to chronic asthma in adulthood. Despite this, current therapies still only treat symptoms. In this issue of Current Drug Targets, nine groups of researchers provide state-of-the-art reviews of critical areas of asthma research ranging from studies on early mechanisms in pediatric cohorts through to adult disease. Each of the reviews relates the state of knowledge to the identification of novel targets that may lead to the development of better treatments for this disease. The issue leads off with Andrew Halayko and colleagues reviewing the current state of knowledge of factors that regulate airway smooth muscle phenotype and function and identifies novel cellular pathways that may serve as targets for future therapeutic initiatives. Steve Stick and John Upham follow on from this; they discuss the cross-talk between airway epithelial cells and dendritic cells as a foundation for the development of new drug targets for use in asthma prevention. The applicability of this strategy to other diseases such as cystic fibrosis and chronic obstructive pulmonary disease is also discussed. The next review by Jane Howell and Robin McAnulty reviews the current knowledge of perhaps the best known growth factor family in wound healing and fibrosis, the TGF-β superfamily and their role in normal and asthmatic airways, as well as the potential for modulating their effects as a therapeutic approach to asthma. Following this, Darren Fernandes and co-workers introduce the extracellular matrix and illustrate its effects on mesenchymal cell phenotype and function. The article also describes the expression and role of specific receptors for extracellular matrix proteins and alludes to their suitability as a molecular target for drug discovery. Lynne Murray, Anuk Das and colleagues then review of the therapeutic potential of chemokines in asthma. This review is timely since clinical trials are currently underway with therapeutics targeting chemokine pathways for a number of other inflammatory diseases. Judith Black and Michael Roth evaluate specific transcription factor abnormalities that they and others have documented are aberrant in asthmatic airways. Since transcription factors play a central role in tissue homeostasis, long term suppression or activation may cause severe side effects in other organs. Thus, cell type specific strategies for manipulating these molecules are also discussed. The next two reviews focus on specific co-factors that potentially influence the expression and function of the pathways and mediators described in the earlier reviews. Del Dorscheid and colleagues review the role of cell surface carbohydrates in epithelial repair. Glycosylation and carbohydrate moieties have been shown to play important role in regulating receptor function during wound repair in a variety of organs and as such offer exciting therapeutic potential. In the next review, Carla Murgia and co-workers review what is currently known about intracellular zinc in the airways, both in the normal and inflamed states, and then considers how developing strategies to monitor and manipulate airway zinc levels in can be used to treat asthma and other inflammatory airway diseases. The final review, by Peter Henry and Ben DeCampo focuses on a relatively newly described family of receptors uniquely activated by protease cleavage. The Protease activated receptors have a myriad of functions that are considered pro- and antiinflammatory and as such their potential as therapeutic targets either by activation or inhibition is being actively researched around the world.

Asthma incidence has climbed markedly in the past two decades despite an increased use of medications that suppress airway inflammation and repress contraction of smooth muscle that encircles the airways. Asthmatics exhibit episodes of airway inflammation that potentiates reversible airway smooth muscle spasm. A hallmark diagnostic symptom of asthma is airway hyperresponsiveness to inhaled non-allergic stimuli, such as methacholine, that directly induce airway smooth muscle contraction. Inhaled gluccocorticoids are used for first-line prevention of airway inflammation, and are frequently combined with inhaled β2-adrenoceptor agonists that can effectively relax airway smooth muscle and restore airway conductance. Leukotriene receptor antagonists and anti-cholinergics can also be used in many patients to ensure optimal control of symptoms. With increasing disease duration irreversible airway restriction develops from inflammation- driven fibro-proliferative airway remodeling that includes increased deposition of extracellular matrix, the accumulation of airway smooth muscle, and increased numbers of myofibroblasts. Mature airway smooth muscle cells are phenotypically plastic, enabling them to subserve contractile, proliferative, migratory and secretory functional responses that contribute to airway remodeling and persistent hyperresponsiveness. This review assesses current understanding of acute and chronic effects of common anti-asthma medications on the diverse phenotype and functional characteristics of airway smooth muscle cells. Furthermore, we describe the significance of these effects in the treatment of asthma symptoms and pathogenesis.

Airway epithelial cells (AEC) and dendritic cells (DC) are situated in close proximity within the airway epithelium, and are the first cells to encounter inhaled pathogens, allergens and environmental pollutants. AEC and DC interact through the release of cytokines and other soluble mediators and through direct cell-cell contact, and these interactions are likely to play an important role in maintaining immune homeostasis. Increasing evidence indicates that both AEC and DC from asthmatic individuals exhibit distinct functional properties, compared with AEC and DC from healthy individuals. Both animal models, and novel co-culture models for directly studying human AEC/DC interactions are providing new insight into the cross-talk between these two important cells types, as a foundation for the development of new drug targets for use in asthma, cystic fibrosis and chronic obstructive pulmonary disease.

Asthma is a chronic disease of the airways affecting around 10% of the population. The majority of cases are well controlled with current therapies, however in approximately 20% of severe asthmatics the available therapeutic strategies are inadequate. Structural changes in the asthmatic airway, including an increase in smooth muscle mass and an increased deposition of extracellular matrix proteins, which correlate with airway hyperresponsivenes, reduced lung function and an increase in fibroblast/myofibroblast numbers, are not specifically targetted by current therapeutic agents and therefore represent an area of unmet need. The mechanisms involved in the development of airway remodelling are incompletely understood but are thought to involve one or more isoforms of transforming growth factor-β (TGF-β). The TGF-βs are pleiotropic mediators which have important roles in the regulation of inflammation, cell growth, differentiation and wound healing. All three mammalian isoforms of TGF-b are present in the airways and at least TGF-β1 and TGF- β2 have been shown to be increased in asthmatic airways and cells, together with evidence of increased TGF-β signalling. In addition, evidence from animal models suggests that airway remodelling may be prevented or reversed using agents which target TGF-β. Therefore modulation of TGF-βs or their activity represent a potential therapeutic target for asthma. This review focuses on the current knowledge of TGF-β1-3, their their role in normal and asthmatic airways, as well as the potential for modulating the TGF-βs and their effects as a therapeutic approach to asthma.

Subepithelial fibrosis is one of the characteristic features of asthmatic airways. The fibrotic response includes an increase in volume occupied by extracellular matrix (ECM) tissue, and a change in the ECM composition favouring wound type collagens, fibronectin and a number of glycoproteins and proteoglycans normally associated with development. The altered ECM is likely to be deposited by the mesenchymal cells (including (myo) fibroblasts and smooth muscle) that are increased in number in asthmatic airways. In turn, the altered asthmatic ECM is likely to influence the function of the resident airway cells, and may be directly responsible for increasing proliferation, migration, ECM synthesis, inflammatory mediator release, and survival of resident mesenchymal cells. Therefore, the deposited ECM may perpetuate the disease phenotype. The different components of the ECM bi-directionally communicate with cells through a family of transmembrane receptors called integrins. Current research has begun to characterize: 1) the particular ECM components altered in airways disease; 2) the breadth of activity of different ECM components on airway cell function; and 3) the particular integrins responsible for mediating these effects. Further understanding of the role of integrins in transmitting responses of ECM in healthy or diseased airways may lead to novel targets for anti-asthma therapy.

The severe asthma phenotype is exhibited by a subset of asthma patients whose asthma symptom is poorly controlled by current therapies. Severe asthma represents a high unmet medical need and warrants research into the mechanisms driving the underlying pathophysiology. It is hypothesized that the underlying pathology associated with severe asthma is driving the symptoms experienced by these patients, which may share common features with mild to moderate asthma or may represent a unique pathological phenotype. For the purpose of this review, the pathophysiology associated with asthma in general are described and extended to incorporate severe asthma. Chemokines may contribute towards multiple features of asthma pathophysiology and this current review focuses on the biology of chemokines pertaining to asthma pathophysiology. Chemokines are important recruiters and activators of inflammatory cells and these infiltrating cells interact with resident cells, such as fibroblasts and it is through these pathways that chemokines appear to exert multiple biological actions. Clinical trials are underway with therapeutics targeting chemokine pathways for other inflammatory diseases. It is hoped that the information generated from these studies will contribute towards furthering our understanding of chemokine biology and be applied towards targeting severe asthma.

The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFκB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkB, Nrf2 or STAT6) or tools (PPARγ, -α and C/EBP-α) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFκB, Nrf2 or STAT6, or specific agonists for PPARγ and -α may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known antiasthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.

Epithelia are the layers of cells that form barriers between external milieu and underlying tissues and thus, are important components of most organs of the body. Epithelial layers of organs, such as the lung, are exposed to various challenges resulting in frequent injury. Epithelial wound healing represents an important process by which repair restores the physical barrier lost as a result of cell damage and apoptosis. The repair of epithelial layers consists of a series of ordered events including epithelial cell spreading, migration proliferation and, differentiation. Carbohydrates attached to cell surface proteins and lipids can modulate the function of structures that they are conjugated to and therefore, can affect cell behavior. Although the basic mechanisms of epithelial repair are not entirely understood, many studies suggest glycoconjugates attached to proteins on the cell surface of epithelial cells play important roles in many of these cellular processes. In the present review, the role of carbohydrates in epithelial repair of different organs, including the sources of epithelial injury and current models of epithelial repair will be discussed with a focus on our understanding of the airway epithelium. With a better understanding of carbohydrates and their role in epithelial repair, new therapeutic targets for diseases involving damage to the epithelium can be identified.

The dietary group IIb metal zinc (Zn) plays essential housekeeping roles in cellular metabolism and gene expression. It regulates a number of cellular processes including mitosis, apoptosis, secretion and signal transduction as well as critical events in physiological processes as diverse as insulin release, T cell cytokine production, wound healing, vision and neurotransmission. Critical to these processes are the mechanisms that regulate Zn homeostasis in cells and tissues. The proteins that control Zn uptake and compartmentalization are rapidly being identified and characterized. Recently, the first images of sub-cellular pools of Zn in airway epithelium have been obtained. This review discusses what we currently know about Zn in the airways, both in the normal and inflamed states, and then considers how we might target Zn metabolism by developing strategies to monitor and manipulate airway Zn levels in airway disease.

Protease-activated receptors (PARs) are characterised by a unique mechanism of activation, which enables them to act as cellular sensors for protease activity. PARs are expressed throughout the cardiovascular, gastrointestinal and pulmonary systems, where they are potential drug targets for the treatment of disease. However, there are currently very few selective PAR antagonists or potent PAR agonists available as effective research tools, and moreover, there is considerable evidence to suggest that PARs can promote both pro-inflammatory and anti-inflammatory responses in a wide range of disease models. These confounding issues have, to date, prevented us from developing a clear understanding of the role of PARs in disease. Nevertheless, this review provides an overview of the distribution and function of PARs in the cardiovascular, gastrointestinal and pulmonary systems, and attempts to evaluate whether PAR agonists or antagonists have a place in future drug therapy.