| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
LPS from bacteria can result in the development of sepsis syndrome and acute lung injury. Although acute exposure to endotoxin primes leukocytes for enhanced synthesis of leukotrienes (LT), little is known about the effect of chronic exposure. Therefore, we determined the effect of prolonged LPS treatment on 5-lipoxygenase (5-LO) metabolism of arachidonic acid in alveolar macrophages (AM) and in peripheral blood monocytes. Pretreatment of AM with LPS caused time- and dose-dependent suppression of LT synthetic capacity. LPS pretreatment failed to inhibit arachidonic acid (AA) release. The fact that LPS inhibited LT synthesis from endogenous AA more than from exogenous AA suggested an effect on 5-LO-activating protein (FLAP). In addition, an inhibitory effect of LPS treatment on AM 5-LO activity was suggested by cell-free 5-LO enzyme assay. No effect on the expression of either 5-LO or FLAP proteins was observed. New protein synthesis was necessary for LPS-induced reduction of 5-LO metabolism in AM, and immunoblotting demonstrated marked induction of NO synthase (NOS). Inhibition by LPS was reproduced by an NO donor and was abrogated by inhibitors of constitutive and inducible NOS. Compared with AM, peripheral blood monocytes exhibited no suppression by LPS of 5-LO metabolism and no induction of inducible NOS. We conclude that prolonged exposure to LPS impairs AM 5-LO metabolism by NO-mediated suppression of both 5-LO and FLAP function. Because LT contribute to antimicrobial defense, this down-regulation of 5-LO metabolism may contribute to the increased susceptibility to pneumonia in patients following sepsis.
This article has been cited by other articles:
|
|
 |
|
  M. Peters-Golden and W. R. Henderson Jr. Leukotrienes N. Engl. J. Med., November 1, 2007; 357(18): 1841 - 1854. [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. Buczynski, D. L. Stephens, R. C. Bowers-Gentry, A. Grkovich, R. A. Deems, and E. A. Dennis TLR-4 and Sustained Calcium Agonists Synergistically Produce Eicosanoids Independent of Protein Synthesis in RAW264.7 Cells J. Biol. Chem., August 3, 2007; 282(31): 22834 - 22847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Serio, C. Luo, L. Luo, and J. T. Mao TNF-{alpha} downregulates the leukotriene C4 synthase gene in mononuclear phagocytes Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L215 - L222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-K. Larsson, M. Back, J. Hjoberg, and S.-E. Dahlen Inhibition of Nitric-Oxide Synthase Enhances Antigen-Induced Contractions and Increases Release of Cysteinyl-Leukotrienes in Guinea Pig Lung Parenchyma: Nitric Oxide as a Protective Factor J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 458 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Antman, D. DeMets, and J. Loscalzo Cyclooxygenase Inhibition and Cardiovascular Risk Circulation, August 2, 2005; 112(5): 759 - 770. [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Serio, K. V. Reddy, and T. D. Bigby Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-{kappa}B and C/EBP-mediated mechanism Am J Physiol Cell Physiol, May 1, 2005; 288(5): C1125 - C1133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Peters-Golden, C. Canetti, P. Mancuso, and M. J. Coffey Leukotrienes: Underappreciated Mediators of Innate Immune Responses J. Immunol., January 15, 2005; 174(2): 589 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Mao, I-H. Tsu, S. M. Dubinett, B. Adams, T. Sarafian, F. Baratelli, M. D. Roth, and K. J. Serio Modulation of Pulmonary Leukotriene B4 Production by Cyclooxygenase-2 Inhibitors and Lipopolysaccharide Clin. Cancer Res., October 15, 2004; 10(20): 6872 - 6878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Abe, M. Hiraoka, S. Wild, S. E. Wilcoxen, R. Paine III, and J. A. Shayman Lysosomal Phospholipase A2 Is Selectively Expressed in Alveolar Macrophages J. Biol. Chem., October 8, 2004; 279(41): 42605 - 42611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Peters-Golden The Alveolar Macrophage: The Forgotten Cell in Asthma Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 3 - 7. [Full Text] [PDF]
|
|
|
|
|
|
N. M. Munoz, Y. J. Kim, A. Y. Meliton, K. P. Kim, S.-K. Han, E. Boetticher, E. O'Leary, S. Myou, X. Zhu, J. V. Bonventre, et al. Human Group V Phospholipase A2 Induces Group IVA Phospholipase A2-independent Cysteinyl Leukotriene Synthesis in Human Eosinophils J. Biol. Chem., October 3, 2003; 278(40): 38813 - 38820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Serio, S. C. Johns, L. Luo, C. R. Hodulik, and T. D. Bigby Lipopolysaccharide Down-Regulates the Leukotriene C4 Synthase Gene in the Monocyte-Like Cell Line, THP-1 J. Immunol., February 15, 2003; 170(4): 2121 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S B Gordon and R C Read Macrophage defences against respiratory tract infections: The immunology of childhood respiratory infections Br. Med. Bull., March 1, 2002; 61(1): 45 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Coffey, S. M. Phare, and M. Peters-Golden Peroxynitrite-Induced Nitrotyrosination of Proteins Is Blocked by Direct 5-Lipoxygenase Inhibitor Zileuton J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 198 - 203. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
