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Infection and Immunity, November 1998, p. 5140-5146, Vol. 66, No. 11
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
5-Lipoxygenase Reaction Products Modulate Alveolar
Macrophage Phagocytosis of Klebsiella pneumoniae
Peter
Mancuso,
Theodore J.
Standiford,
Teresa
Marshall, and
Marc
Peters-Golden*
Division of Pulmonary and Critical Care
Medicine, Department of Internal Medicine, University of Michigan
Medical Center, Ann Arbor, Michigan 48109-06421
Received 8 April 1998/Returned for modification 1 June
1998/Accepted 5 August 1998
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.
*
Corresponding author. Mailing address: Division of
Pulmonary and Critical Care Medicine, 6301 MSRB III, University of
Michigan Medical Center, Ann Arbor, MI 48109-0642. Phone: (734)
763-9077. Fax: (734) 764-4556. E-mail:
petersm{at}medmail.med.umich.edu.
Infection and Immunity, November 1998, p. 5140-5146, Vol. 66, No. 11
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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