AP-1 as a potential therapeutic target in allergic airways inflammation

Asthma is characterized by a complex inflammatory response of airways eosinophilia, edema, mucus hypersecretion and hyperactivity that is accompanied by structural changes of the airways, termed airways remodeling. Airways remodeling in asthma results in alterations in the airways epithelium, lamina propria and submucosa, leading to thickening of the airways wall. Bronchoalveolar lavage (BAL), biopsy and autopsy data indicate that the severity of the disease is correlated with increased T-helper cell type 2 (Th2) cytokines (IL-4, IL-5 and IL-13). These changes may predispose asthma patients to exacerbations and even death due to airways obstruction. Over the last decade there has been a growing appreciation that chronic airways inflammation is integral to the development of severe asthma and underlies the development of airways hyperactivity. Consequently, increasing emphasis has been placed on the treatment of the underlying inflammatory component of asthma rather than physiological antagonism of the airways smooth muscle response. Most existing asthma treatments treat either the acute bronchoconstriction (beta-agonists) or a portion of the acute inflammatory response (leukotriene antagonists), or they have severe dose-limiting side effects (corticosteroids). In this review, we describe the feasibility of inhibiting a novel drug target, the AP-1 transcription factor, as a therapy for asthma. AP-1 elements and AP-1 activation are associated with the transcription of a variety of Th2 cytokines, as well as other inflammatory mediators.