Mechanisms of aspirin-intolerant asthma: identifying inflammatory pathways in the pathogenesis of asthma.

pathway to form the leukotriene, LTA 4 . LTA 4 is an unstable compound and is rapidly metabolized to either LTB 4 or the cysteinyl leukotrienes (CysLTs). The CysLTs are leukocyte chemoattractants and bronchoconstrictors. In addition to COX and 5-LO pathways, 15-lipoxygenase catalyzes the hydroperoxidation of arachidonic acid to form 15-HPETE which is then further metabolized to form 15-HETE and the lipoxins and eoxins. Aspirin causes irreversible inhibition of COX-1 and competes directly with arachidonic acid for binding to the COX site. The proposed mechanism of AIA is the generation of increased levels of CysLTs as a result of increased levels of precursors due the inhibition of COX by aspirin. Eosinophils generate large amounts of CysLTs, and the appearance of increased levels of eosinophils in the bronchial musosa has been observed in AIA [3] . It has also previously been shown that that activated sputum eosinophils from subjects with AIA produce increased levels of CysLTs ex vivo [4] . This is the first data that define the release of arachidonic acid metabolites from blood eosinophils from well-characterized subjects with AIA. In addition, the responses of normal subjects and differing severities of asthma were studied, allowing the effect of dose of inhaled steroid to be investigated. Much attention has been paid to the biological role of 5-LO, but relatively little is known about 15-LO and its Asthma is a disease that is associated with considerable morbidity, and still has an associated mortality. Corticosteroids remain the main effective treatment for asthma, but these are associated with potentially serious side effects. Identification of inflammatory pathways in the pathogenesis of asthma allows new therapeutic targets to be proposed. There is a subset of patients with asthma who experience an exacerbation of their asthma when they take aspirin, so-called aspirin-intolerant asthma (AIA). The association between aspirin and asthma has been known since 1922 when it was first described by Widal [1] ; however, it only received widespread recognition in the 1960s when Samter and Beers [2] published the association between asthma, nasal polyps and aspirin sensitivity, subsequently referred to as Samter’s triad. The recognition of aspirin-sensitive asthma has significant implications for patient management, as patients with AIA are more likely to have more severe disease and to develop irreversible airflow obstruction. The mechanism of AIA is due to effects on the metabolism of arachidonic acid. Arachidonic acid is a component of cell walls and is released by the action of cytosolic phospholipase A 2 . Arachidonic acid can then be metabolized through the cyclooxygenase (COX) pathway to form prostanoids or through the 5-liopoxygenase (5-LO) Published online: November 16, 2013