5-LIPOXYGENASE REACTION-PRODUCTS MODULATE ALVEOLAR MACROPHAGE PHAGOCYTOSIS OF KLEBSIELLA-PNEUMONIAE

The leukotrienes are potent lipid mediators of inflammation formed by the 5-lipoxygenase-catalyzed oxidation of arachidonic acid. Although t he effects of leukotrienes on neutrophil chemotaxis and activation hav e been established, their role in modulating innate host defense mecha nisms is poorly understood. In a previous study (M. Bailie, T. Standif ord, L. Laichalk, M. Coffey, R Stricter, and M. Peters-Golden, J. Immu nol. 157: 5221-5224, 1996), we used 5-lipoxygenase knockout mice to es tablish a critical role for endogenous leukotrienes in pulmonary clear ance and alveolar macrophage phagocytosis of Klebsiella pneumoniae. In the present study, we investigated the role of specific endogenous le ukotrienes in phagocytosis of K. pneumoniae and explored the possibili ty that exogenous leukotrienes could restore phagocytosis in alveolar macrophages with endogenous leukotriene synthesis inhibition and enhan ce this process in leukotriene-competent cells. Rat alveolar macrophag es produced leukotriene B-4 (LTB4), LTC4, and 5-hydoxyeicosatetraenoic acid (5-HETE) during the process of phagocytosis, and the inhibition of endogenous leukotriene synthesis with zileuton and MK-886 dramatica lly attenuated phagocytosis. We also observed a reduction in phagocyto sis when we treated alveolar macrophages with antagonists to the plasm a membrane receptors for either LTB4, cysteinyl-leukotrienes, or both. In leukotriene-competent cells, LTC, augmented phagocytosis to the gr eatest extent, followed by 5-HETE and LTE,. These 5-lipoxygenase react ion products demonstrated similar relative abilities to reconstitute p hagocytosis in zileuton-treated rat alveolar macrophages and in alveol ar macrophages from 5-lipoxygenase knockout mice. We conclude that end ogenous synthesis of all major 5-lipoxygenase reaction products plays an essential role in phagocytosis. The restorative and pharmacologic e ffects of LTC4, LTB4, and 5-HETE may provide a basis for their exogeno us administration as an adjunctive treatment for patients with gram-ne gative bacterial pneumonia.