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Rethinking the Pathogenesis of Asthma
Stephen T. Holgate1,* and Donna E. Davies1
1III Division, School of Medicine, University of Southampton, Southampton S016 61D, UK *Correspondence: DOI 10.1016/j.immuni.2009.08.013

Asthma research has focused primarily on allergic pathways on the basis that the majority of asthma is associated with atopy, therecruitment of the Th2-type T cell, the cytokines, and the chemokines that are released on exposure to allergens, and the IgE pathway. However, despite considerable investment by industry, targeting these pathways has not resulted in new treatments being developed beyond blockade of cysteinyl leukotrienes and IgE and improvements in inhaled corticosteroids and b2-adrenoceptor bronchodilators.Increasingly, it is recognized that asthma is a heterogeneous disorder, and while important, allergen sensitization is only one component of the disease, with many other environmental and genetic factors playing a role. In addition, these factors act locally on a susceptible airway epithelium that is both structurally and functionally deficient. It may be worthwhile to focus on increasing the resilience ofthe airways to environmental insults in addition to improving strategies that modify adaptive immunity or suppress inflammation.
Current Shortfalls in Understanding Asthma Pathogenesis Asthma is a common disease that afflicts all ages and can vary greatly in severity. It is primarily an inflammatory disorder of the conducting airways upon which is superimposed both an increase in smooth muscle and achange in its responsiveness to stimulation that manifests clinically as variable airflow obstruction. The disease is also characterized by varying degrees of airway-wall remodeling linked to more fixed airflow obstruction and a gradual decline in lung function over time. Another degree of complexity is the wide number of environmental factors associated with the inception of asthma, itspersistence, and its acute deterioration (exacerbations) that include exposure to inhaled allergens, air pollutants, certain drugs, occupational chemicals, and environmental tobacco smoke. Most frequently, asthma begins in early childhood, although the factors that contribute to its origin are still not known. Its course can vary widely over time, with up to half the children entering into remission duringthe adolescent and young adult years but with a propensity to return later in life again through mechanisms that are poorly understood. One reason why we know so little about those factors that contribute to its origin and the different phenotypes that ensue is because, until relatively recently, asthma has not been studied across the life course. Even in late-onset asthma in adults, we know littleabout those factors that initiate the disease other than to the form associated with exposure to occupational chemicals. In the case of nonallergic asthma, where there is a conspicuous absence of atopy, almost nothing is known about its origins or how and why it can persist. From a therapeutic standpoint, asthma is mostly managed with a combination of short- and long-acting bronchodilators andinhaled corticosteroids that target the inflammatory and smooth muscle responses. Although effective in the majority of patients, this approach to management falls a long way short of being ideal, as reflected by low patient adherence to treatment, dependency on the use of inhaled drugs (sometimes for life), and the remaining unmet clinical need, especially from exacerbations, at the severe end of thedisease spectrum (approximately 10%). Patient-based surveys of asthma conducted in many countries all reveal similar findings of a persisting disease burden and impaired quality of life (Holgate et al., 2008). This does not mean that progress has not been made over the last two decades. Indeed, the introduction of management guidelines initially focused on a stepwise approach to drug use but...
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