Leukotriene B 4 Augments Neutrophil Phagocytosis of

Neutrophils play a critical role in the clearance of bacteria from the lung and other organs by their capacity for phagocytosis and killing. Previously, we identified an important role for the leukotrienes in rat alveolar macrophage phagocytosis of Klebsiella pneumoniae. In this report, we explored the possibility that the leukotrienes play an important role in phagocytosis by neutrophils as well. Inhibition of endogenous leukotriene synthesis by 5-lipoxygenase knockout in mice or by pharmacologic means in human peripheral blood neutrophils attenuated phagocytosis of opsonized K. pneumoniae. Reduced phagocytosis was also observed in human neutrophils pretreated with a leukotriene B4 receptor but not a cysteinyl-leukotriene receptor antagonist. While leukotriene B4 reconstituted defective phagocytosis in leukotriene-deficient neutrophils and enhanced phagocytosis in neutrophils capable of leukotriene synthesis, leukotriene C4, leukotriene D4, 5-hydroperoxyeicosatetraenoic acid, and 5-oxo-eicosatetraenoic acid were ineffective. To determine the opsonin dependence of the leukotriene B4 augmentation of phagocytosis, we assessed the ability of leukotriene B4 to modulate neutrophil phagocytosis and the adherence of sheep erythrocytes opsonized with immunoglobulin G or the complement fragment C3bi. While leukotriene B4 augmented both Fc receptor- and complement receptor-mediated phagocytosis, increased adherence to leukotriene B4-treated neutrophils was limited to complement opsonized targets. In conclusion, we have identified a novel role for leukotriene B4 in the augmentation of neutrophil phagocytosis mediated by either the Fc or complement receptor. The alveolar epithelial surface represents the body’s largest interface with the external environment, and it is continually challenged with bacteria aspirated from the oropharynx that evade the mechanical clearance mechanisms of the upper respiratory tract. The alveolar macrophage (AM) is the primary means of innate host defense against bacterial pathogens that attempt to reach the alveolar space. When the bacterial burden in the alveolar space is great enough to activate a sufficient number of AMs to secrete chemotactic substances such as chemokines, leukotriene B4 (LTB4), and complement fragments, polymorphonuclear leukocytes (PMNs) are recruited from a marginated pool in the pulmonary vasculature to the alveolar epithelial surface (19). PMNs play a critical role in clearing encapsulated bacteria, such as Klebsiella pneumoniae, from the lung and in preventing bacterial dissemination to the systemic circulation (26). The ability of these cells to perform this function can be enhanced by inflammatory mediators that activate the PMN for increased phagocytosis and killing of ingested bacteria. The LTs are potent lipid mediators of inflammation derived from the 5-lipoxygenase (5-LO)-catalyzed oxygenation of arachidonic acid (AA). The enzyme 5-LO in concert with the 5-LO activating protein can oxygenate AA to form the intermediate metabolite, 5-hydroperoxyeicosatetraenoic acid. This 5-LO product can either be dehydrated to LTA4 or reduced to 5-hydroxyeicosatetraenoic acid (5-HETE). LTA4 can be hydrolyzed to form the potent PMN chemoattractant LTB4 or conjugated with glutathione to form the cysteinyl-LTs (LTC4,