Role of Leukotrienes in Bronchial Hyperresponsiveness and Cellular Responses in Airways

Among constitutively present cells, bronchoactive leukotrienes are produced predominantly by mast cells (1) and macrophages (2). A unique characteristic of asthmatic inflammation is the migration of leukocytes from the peripheral blood to the conducting airways of the lung. This is especially true of the eosinophil, which is not present in the airways of normal individuals, but may be found in massive numbers during periods of airway hyperresponsiveness in asthmatic individuals [Figure 1 (3)] (4-6). Most experimental models indicate that eosinophils are an invariable component of asthmatic hyperresponsiveness, although some studies suggest that bronchoconstriction can occur in the relative absence of these cells. For the purposes of this discussion, the eosinophil is viewed as a leukotriene transport system capable of providing a substantial reservoir of bronchoactive leukotrienes to airways in a relatively short time. They may be delivered to conducting airways in large numbers and have the capacity to produce cysteinyl-leukotriene C 4 (Cys-LTC 4 ), which cannot be produced by neutrophils, but also migrate into conducting airways in some circumstances (7, 8). This discussion deals first with the mechanism by which eosinophils, a minority constituent of the circulating blood, are homed selectively to the conducting airways of the lung in human asthma. The mechanism by which the recruitment process of cellular adhesion primes migrating eosinophils for augmented leukotriene synthesis is discussed with particular reference to interactions between surface integrins on eosinophils and their counterligands, the immunoglobulin supergenes on the endothelial surface (9, 10) and fibronectin within the airway wall (11). The potential physiological significance of augmented secretion caused by adhesive interactions is suggested by experiments elucidated in this discussion. Finally, some new preliminary evidence for an autocrine mechanism of eosinophil recruitment that is mediated through the secretion of Cys-leukotrienes is considered.