Priming of alveolar macrophages by leukotriene D-4 - Potentiation of inflammation

Cysteinyl leukotrienes (LTs), including LTC4, LTD4, and LTE4, are well know n to induce bronchoconstriction and increase bronchial hyperreactivity, muc us secretion, and vascular permeability. Interestingly, alveolar macrophage s (AMs) express LTD4 high-affinity receptor. These cells represent a major source of inflammatory mediators implicated in the pathophysiology of asthm a. Thus, we investigated the immunomodulatory effects of LTD4 on the produc tion of inflammatory mediators such as macrophage inflammatory protein (MIP )-1 alpha, tumor necrosis factor (TNF), and nitric oxide (NO) by AMs. NR838 3 cells, an AM cell line, were pretreated with LTD4 (10(-11) M) for differe nt periods of time and stimulated or not with lipopolysaccharide (LPS) for 2 h. Although LTD4 treatment did not modulate the release of MIP-1 alpha an d TNF, this treatment (6 h) significantly increased the release of these me diators when AMs were further stimulated with LPS (increases of 47 and 21%, respectively). Further, LTD4 pretreatment increased messenger RNA (mRNA) l evels of MIP-1 alpha and TNF. These effects of LTD4 were abrogated by the p resence of a LTD4 receptor antagonist, Verlukast (MK-679), showing the spec ificity of LTD4. Interestingly, LTD4 treatment significantly increased the release of NO by LPS-stimulated AMs without modulating mRNA levels of the i nducible NO synthase. Our data suggest that LTD4 primes AMs to release more MIP-1 alpha, TNF, and NO after stimulation. Thus, in addition to its poten t bronchoconstrictor effect, LTD4 may participate in the inflammatory proce ss seen in asthma by potentiating the production of proinflammatory mediato rs by AMs during immunologic stimuli.