Phagocytosis and bactericidal action of mouse peritoneal macrophages treated with leukotriene B4

Leukotrienes (LTs) are considered important for antibacterial defense in the lung. Multidrug resistance protein 1 (mrp1) is a transmembrane protein responsible for the cellular extrusion of LTC4. To determine the role of mrp1 in host defense against pneumonia, mrp1−/− and wild-type mice were intranasally inoculated with Streptococcus pneumoniae. mrp1−/− mice displayed a diminished outgrowth of pneumococci in lungs and a strongly reduced mortality. These findings were related to an effect of mrp1 on LT metabolism, because survival was similar in mrp1−/− and wild-type mice treated with the 5-lipoxygenase-activating protein inhibitor MK-886. Although LTC4 levels remained low in the bronchoalveolar lavage fluid of mrp1−/− mice, LTB4 concentrations were higher than in wild-type mice. These elevated LTB4 concentrations were important for the relative protection of mrp1−/− mice, because the LTB4 antagonist LTB4-dimethyl amide abolished their survival advantage. In vitro experiments suggested that the intracellullar accumulation of LTC4 in mrp1−/− mice results in product inhibition of LTC4-synthase, diminishing substrate competition between LTA4-hydrolase (which yields LTB4) and LTC4-synthase for the available LTA4. We conclude that mrp1−/− mice are resistant against pneumococcal pneumonia by a mechanism that involves increased release of LTB4. These results identify mrp1 as a novel target for adjunctive therapy in pneumonia.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mice Lacking the Multidrug Resistance Protein 1 Are Resistant to Streptococcus pneumoniae-Induced Pneumonia

Schultz

Wijnholds

Peppelenbosch³

et al. 2001

“…An in vivo role for LTs in antimicrobial defense was first suggested by Demitsu et al (33), who showed that i.p. administration of LTB 4 facilitated resolution of experimental bacterial peritonitis.…”

Section: Antimicrobial Effector Functions Of Ltsmentioning

confidence: 97%

“…bolus to normal subjects and was shown to dosedependently increase plasma levels of the antibacterial peptide ␣-defensin and the chemokine MIP-1␤ (53). Local LTB 4 administration has been shown to reduce the peritoneal burden of bacteria in an animal model of peritonitis (33), and it has also been administered to the human lung via aerosol (97) or via a bronchoscope (98) and resulted in neutrophil influx without evidence of lung injury or other adverse effects. As compared with administration of a protein, direct administration of a lipid such as LTB 4 has the advantages of being less immunogenic, shorter-lived, and less expensive.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

279

244

Leukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.

“…Whether LTB 4 could be a useful immunostimulant for the treatment of infectious diseases remains to be investigated in clinical trials; numerous animal studies have already reported a beneficial effect of this eicosanoid models of infection (57)(58)(59)(60)(61)(62)(63)(64). LTB 4 administration to humans has been documented (29,65,66), with pharmacodynamic effects (␣-defensin and MIP-1␤ release (29) and PMN count variations (our unpublished data)) similar to what is reported in this study in monkeys without significant adverse events.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Flamand

Tremblay

Borgeat

2007

Leukotriene B4 (LTB4) is a bioactive lipid derived from the metabolism of arachidonic acid. Mainly produced by polymorphonuclear leukocytes (PMN) and macrophages, LTB4 triggers several functional responses important in host defense, including the secretion of lysosomal enzymes, the activation of NADPH oxidase activity, NO formation, and phagocytosis. We report that LTB4, but not structural analogs thereof, stimulates primed human PMN to release molecules having potent antimicrobial activities. Exposure of bacteria (Escherichia coli and Staphylococcus aureus) or viruses (herpes simplex virus type 1 and HIV type 1) to supernatants of LTB4-activated PMN lead to ≥90% reduction in infectivity. ELISA and mass spectroscopy analysis of proteins released from LTB4-activated PMN have identified several antimicrobial proteins, including α-defensins, cathepsin G, elastase, lysozyme C, and LL-37, that are likely to participate in the killing of microorganisms. In addition to these in vitro observations, i.v. injections of LTB4 (50 μg/kg) to monkeys led to an increase in α-defensin plasmatic levels and enhanced ex vivo antimicrobial activities of plasma. These results demonstrate the ability of LTB4 to cause the release of potent antimicrobial agents from PMN in vitro as well as in vivo and add further support to the important role of LTB4 in host defense.