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 the effects of leukotrienes on neutrophil chemotaxis and activation have been established, their role in modulating innate host defense mechanisms is poorly understood. In a previous study (M. Bailie, T. Standiford, L. Laichalk, M. Coffey, R. Strieter, and M. Peters-Golden, J. Immunol. 157:5221-5224, 1996), we used 5-lipoxygenase knockout mice to establish a critical role for endogenous leukotrienes in pulmonary clearance and alveolar macrophage phagocytosis of Klebsiella pneumoniae. In the present study, we investigated the role of specific endogenous leukotrienes in phagocytosis of K. pneumoniae and explored the possibility that exogenous leukotrienes could restore phagocytosis in alveolar macrophages with endogenous leukotriene synthesis inhibition and enhance this process in leukotriene-competent cells. Rat alveolar macrophages produced leukotriene B4 (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 dramatically attenuated phagocytosis. We also observed a reduction in phagocytosis when we treated alveolar macrophages with antagonists to the plasma membrane receptors for either LTB4, cysteinyl-leukotrienes, or both. In leukotriene-competent cells, LTC4 augmented phagocytosis to the greatest extent, followed by 5-HETE and LTB4. These 5-lipoxygenase reaction products demonstrated similar relative abilities to reconstitute phagocytosis in zileuton-treated rat alveolar macrophages and in alveolar macrophages from 5-lipoxygenase knockout mice. We conclude that endogenous synthesis of all major 5-lipoxygenase reaction products plays an essential role in phagocytosis. The restorative and pharmacologic effects of LTC4, LTB4, and 5-HETE may provide a basis for their exogenous administration as an adjunctive treatment for patients with gram-negative bacterial pneumonia.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA. petersm@medmail.med.umich.edu
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Mancuso
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Standiford
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Marshall
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Peters-Golden
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D007711:Klebsiella pneumoniae / Q000276:immunology*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects
D020024:Leukotriene Antagonists; D015289:Leukotrienes; D009895:Opsonin Proteins; D011956:Receptors, Cell Surface; D001094:Arachidonate 5-Lipoxygenase