Unilamellar liposomes modulate secretion of tumor necrosis factor by lipopolysaccharide-stimulated macrophages

Abstract

Liposomal encapsulation of antimicrobial agents has been used to improve drug delivery, particularly against intracellular pathogens. The effect of unilamellar liposomes on macrophage activation in response to Escherichia coli lipopolysaccharide was examined. Liposomes caused a dose-and time-dependent inhibition of tumor necrosis factor release by lipopolysaccharide-treated cells. The accumulation of tumor necrosis factor mRNA transcripts was unaffected, suggesting a posttranscriptional mechanism for this effect. However, induction of macrophage procoagulant activity was unaffected by liposomes, indicating a selective rather than a global inhibition. These data suggest that liposomes used for drug delivery may modulate the host response to infection.Standard therapy for the management of secondary bacterial peritonitis includes fluid resuscitation to restore normal hemodynamics, surgical intervention to deal with the underlying pathological process and to reduce the bacterial inoculum, and the use of antimicrobial agents to treat local and systemic infections. Despite modem therapeutic approaches, clinical failures occur, some of which are attributed to antibiotic failure. The reasons for the lack of efficacy of various antimicrobial regimens include bacterial resistance, inadequate antibiotic levels, the failure of antibiotics to penetrate into sites of residual infection, and the reduced levels of antibiotic activity within the abnormal microenvironment of infection. Various novel approaches have been used to overcome some of these deficiencies. Liposome-encapsulated antibiotics have been shown to have improved penetration into phagocytic cells and have been advocated for use against intracellular microbes (1,22). Indeed, this carrier system augmented the efficacy of various antimicrobial agents against a wide range of microorganisms that survive within macrophages (1, 6, 9, 25). Our laboratory -has previously reported that the use of cefoxitin encapsulated within unilamellar liposomes (95% dipalmitoylphosphatidylcholine, 5% phosphatidylserine) significantly reduced the mortality rate compared with that with the use of free cefoxitin in an intra-abdominal infection model in the rat (5). Improved survival correlated with a reduction in residual bacterial numbers in the peritoneal cavity and the liver, suggesting that the beneficial effect of liposome-encapsulated cefoxitin was mediated via the improved microbicidal activity.Experimental intra-abdominal infection has been shown to initiate the release of numerous cytokines by cells of the monocyte/macrophage lineage (11). Among these, tumor necrosis factor (TNF) appears to play a central role in the host response to infection, including the lethality associated with endotoxemia (3,13,17,26,27 595-9486. ment with anti-TNF antibodies prevents the hemodynamic and pathological alterations as well as the lethal effects of endotoxin administration. On the basis of the importance of TNF in the development of the host response to intra-abdominal infection, we hypoth...

Reduction of NO Synthase Expression and Tumor Necrosis Factor Alpha Production in Macrophages by Amphotericin B Lipid Carriers

“…Phosphatidylglycerol was not tested. On the other hand, negatively charged unilamellar liposomes containing 5% phosphatidylserine were observed to inhibit TNF-␣ by a posttranslational mechanism (7). Again, the concentration of lipid which gave significant inhibition (6 mM) was higher than that used in our experiments.…”

Liposomal NAD+prevents diminished O2consumption by immunostimulated Caco-2 cells

“…We are not prepared to an offer an explanation for this effect but would speculate that the liposomes had an immunomodulatory effect, as has been reported previously in some other systems (2,7).…”

Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice

“…Although TNF-α aids in the bacterial clearance process, excessive production of this cytokine during infection leads to uncontrolled inflammation (cytokine storm), and increased mortality. Liposomes that contain negatively charged phosphatidylserine have been shown to inhibit TNF-α-release from lipopolysaccharide (LPS)-treated cells 28 . The liposomes used in this study did not contain phosphatidylserine, and their protective action was not due to an inhibition of LPS-induced TNF-α overproduction.…”