Editorial [Hot Topic: New Drug Targets for the Treatment of Asthma (Guest Editor: D. Knight)]

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.